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1
Islam, Saiful, Theodosia Teo, Malika Kumarasiri, Martin Slater, Jennifer H. Martin, Shudong Wang, and Richard Head. "Combined In Silico and In Vitro Evidence Supporting an Aurora A Kinase Inhibitory Role of the Anti-Viral Drug Rilpivirine and an Anti-Proliferative Influence on Cancer Cells." Pharmaceuticals 15, no. 10 (September 25, 2022): 1186. http://dx.doi.org/10.3390/ph15101186.
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The global burden of cancer necessitates rapid and ongoing development of effective cancer therapies. One promising approach in this context is the repurposing of existing non-cancer drugs for cancer indications. A key to this approach is selecting the cellular targets against which to identify novel repurposed drugs for pre-clinical analysis. Protein kinases are highly sought-after anticancer drug targets since dysregulation of kinases is the hallmark of cancer. To identify potential kinase-targeted drug candidates from the existing portfolio of non-cancer therapeutics, we used combined in silico and in vitro approaches, including ligand-based 3D screening followed by biochemical and cellular assessments. This strategy revealed that the anti-viral drug rilpivirine is an Aurora A kinase inhibitor. In view of previous findings implicating Aurora A kinase in abnormal cell cycle regulation, we also examined the influence of rilpivirine on the growth of T47D breast cancer cells. Herein, we detail the identification of rilpivirine as an Aurora A kinase inhibitor, its molecular basis of inhibitory activity towards this kinase, and its Aurora A-mediated anticancer mechanisms in T47D cells. Our results illustrate the value of integrated in silico and in vitro screening strategies in identifying repurposed drug candidates and provide a scientific basis for further exploring the potential anticancer properties of the anti-viral drug rilpivirine.
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Pereira Moreira, Bernardo, Michael H. W. Weber, Simone Haeberlein, Annika S. Mokosch, Bernhard Spengler, Christoph G. Grevelding, and Franco H. Falcone. "Drug Repurposing and De Novo Drug Discovery of Protein Kinase Inhibitors as New Drugs against Schistosomiasis." Molecules 27, no. 4 (February 19, 2022): 1414. http://dx.doi.org/10.3390/molecules27041414.
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Schistosomiasis is a neglected tropical disease affecting more than 200 million people worldwide. Chemotherapy relies on one single drug, praziquantel, which is safe but ineffective at killing larval stages of this parasite. Furthermore, concerns have been expressed about the rise in resistance against this drug. In the absence of an antischistosomal vaccine, it is, therefore, necessary to develop new drugs against the different species of schistosomes. Protein kinases are important molecules involved in key cellular processes such as signaling, growth, and differentiation. The kinome of schistosomes has been studied and the suitability of schistosomal protein kinases as targets demonstrated by RNA interference studies. Although protein kinase inhibitors are mostly used in cancer therapy, e.g., for the treatment of chronic myeloid leukemia or melanoma, they are now being increasingly explored for the treatment of non-oncological conditions, including schistosomiasis. Here, we discuss the various approaches including screening of natural and synthetic compounds, de novo drug development, and drug repurposing in the context of the search for protein kinase inhibitors against schistosomiasis. We discuss the status quo of the development of kinase inhibitors against schistosomal serine/threonine kinases such as polo-like kinases (PLKs) and mitogen-activated protein kinases (MAP kinases), as well as protein tyrosine kinases (PTKs).
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Patel, Gautam, Norma E. Roncal, Patricia J. Lee, Susan E. Leed, Jessey Erath, Ana Rodriguez, Richard J. Sciotti, and Michael P. Pollastri. "Repurposing human Aurora kinase inhibitors as leads for anti-protozoan drug discovery." Med. Chem. Commun. 5, no. 5 (2014): 655–58. http://dx.doi.org/10.1039/c4md00045e.
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Hesperadin, an established human Aurora B inhibitor, was tested against cultures of Trypanosoma brucei, Leishmania major, and Plasmodium falciparum, and was identified to be a potent proliferation inhibitor.
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Regan-Fendt, Kelly, Ding Li, Ryan Reyes, Lianbo Yu, Nissar A. Wani, Peng Hu, Samson T. Jacob, Kalpana Ghoshal, Philip R. O. Payne, and Tasneem Motiwala. "Transcriptomics-Based Drug Repurposing Approach Identifies Novel Drugs against Sorafenib-Resistant Hepatocellular Carcinoma." Cancers 12, no. 10 (September 23, 2020): 2730. http://dx.doi.org/10.3390/cancers12102730.
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Objective: Hepatocellular carcinoma (HCC) is frequently diagnosed in patients with late-stage disease who are ineligible for curative surgical therapies. The majority of patients become resistant to sorafenib, the only approved first-line therapy for advanced cancer, underscoring the need for newer, more effective drugs. The purpose of this study is to expedite identification of novel drugs against sorafenib resistant (SR)-HCC. Methods: We employed a transcriptomics-based drug repurposing method termed connectivity mapping using gene signatures from in vitro-derived SR Huh7 HCC cells. For proof of concept validation, we focused on drugs that were FDA-approved or under clinical investigation and prioritized two anti-neoplastic agents (dasatinib and fostamatinib) with targets associated with HCC. We also prospectively validated predicted gene expression changes in drug-treated SR Huh7 cells as well as identified and validated the targets of Fostamatinib in HCC. Results: Dasatinib specifically reduced the viability of SR-HCC cells that correlated with up-regulated activity of SRC family kinases, its targets, in our SR-HCC model. However, fostamatinib was able to inhibit both parental and SR HCC cells in vitro and in xenograft models. Ingenuity pathway analysis of fostamatinib gene expression signature from LINCS predicted JAK/STAT, PI3K/AKT, ERK/MAPK pathways as potential targets of fostamatinib that were validated by Western blot analysis. Fostamatinib treatment reversed the expression of genes that were deregulated in SR HCC. Conclusion: We provide proof of concept evidence for the validity of this drug repurposing approach for SR-HCC with implications for personalized medicine.
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Ferrarelli, Leslie K. "Repurposing an HIV drug for melanoma." Science Signaling 9, no. 423 (April 12, 2016): ec85-ec85. http://dx.doi.org/10.1126/scisignal.aaf8440.
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Inhibitors of the kinases BRAF or MEK (BRAF/MEK) can reduce tumor growth in some patients with melanoma, but resistance often develops. Microphthalmia-associated transcription factor (MITF) is implicated in promoting melanoma development. Smith et al. found that long-term treatment of cell cultures and mice bearing xenografts with BRAF/MEK inhibitors increased the abundance of MITF and its transcription factor PAX3 and that silencing MITF sensitized drug-resistant melanoma cells to the inhibitors. In a screen for small molecules that could reduce the abundance of MITF or PAX3, the most effective drug was nelfinavir mesylate, a protease inhibitor currently used to treat human immunodeficiency virus (HIV) infection. Nelfinavir sensitized melanoma cells to BRAF/MEK inhibitors but not in the context of ectopic overexpression of PAX3 or MITF. PAX3 abundance is suppressed by the transcriptional repressor SKI, which functions in complex with the transforming growth factor–β (TGF-β) effectors SMAD2 and SMAD4. BRAF/MEK inhibitors decreased the amount of SKI at the PAX3 promoter. Nelfinavir increased the amount of total as well as nuclear, phosphorylated (activated) SMAD2, the amount of SMAD2/SMAD4/SKI complexes, and the amount of SKI bound to the PAX3 promoter and consequently reduced the abundance of PAX3 and MITF. Nelfinavir could not reduce MITF abundance in the absence of SMAD4. The findings indicate that by counteracting the effects of BRAF/MEK inhibitors on SMAD2/SMAD4/SKI transrepression of PAX3, nelfinavir may be able to prevent drug resistance in melanoma; however, it is not yet clear through which proteases nelfinavir mediates these effects on SMAD2 and SKI. Furthermore, because MITF suppression is conversely associated with metastatic disease, the immediate clinical application of nelfinavir for melanoma patients is cautioned against (see Kim and Ronai). With further investigation, the findings of Smith et al. suggest that patients might be selected for nelfinavir-based therapy based on early-stage disease and tumor cell markers, such as the abundances of SMAD2, SMAD4, and SKI.M. P. Smith, H. Brunton, E. J. Rowling, J. Ferguson, I. Arozarena, Z. Miskolczi, J. L. Lee, M. R. Girotti, R. Marais, M. P. Levesque, R. Dummer, D. T. Frederick, K. T. Flaherty, Z. A. Cooper, J. A. Wargo, C. Wellbrock, Inhibiting drivers of non-mutational drug tolerance is a salvage strategy for targeted melanoma therapy. Cancer Cell 29, 270–284 (2016). [PubMed] H. Kim, Z. A. Ronai, HIV drug to aid melanoma therapies? Cancer Cell 29, 245–246 (2016). [PubMed]
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Yu, Ga-Ram, Seung-Jun Lee, Dong-Woo Lim, Hyuck Kim, Jai-Eun Kim, and Won-Hwan Park. "Drug Repurposing in Alternative Medicine: Sochehwan, a Polyherbal Traditional Korean Digestant, Protects against Alcoholic Steatohepatitis by Regulating Cytochrome P450 2E1 Expression." Processes 9, no. 10 (September 30, 2021): 1760. http://dx.doi.org/10.3390/pr9101760.
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Sochehwan (SCH) is an herbal prescription from traditional oriental medicine and is currently used to treat digestive ailments. In a previous study, SCH was found to have the potential to attenuate metabolic syndrome (MetS) by activating AMPK and downstream signaling. From the view of drug repurposing, the efficacy of SCH on alcoholic liver injury is implied in classic medical texts but is yet to be proven. C57BL/6J mice were pre-treated with SCH orally for 5 days and challenged by providing a pair-fed Lieber DeCarli diet containing alcohol for 20 days. Hepatic enzyme and triglyceride levels and endoplasmic reticulum (ER) stress-related markers were analyzed. Moreover, mitogen-activated protein kinases (MAPKs) and cytochrome P450 2E1 (CYP2E1) levels were determined. CYP2E1-transfected HepG2 cells were used to test the cytoprotective efficacy of SCH against the adverse effects of alcohol in vitro. In mice, SCH administration notably reduced hepatic enzyme activity and neural lipid levels. Furthermore, ER-stress markers and MAPK phosphorylation were reduced due to ROS suppression, which was attributed to decreased CYP2E1 expression in liver tissue. In addition, SCH successfully protected CYP2E1-transfected HepG2 cells against ethanol. Our findings suggest SCH attenuated alcohol-induced liver injury by inhibiting CYP2E1 expression and indicate drug repurposing should be considered as a valuable option for drug development in traditional herbal medicines.
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Thirunavukkarasu, Muthu Kumar, Utid Suriya, Thanyada Rungrotmongkol, and Ramanathan Karuppasamy. "In Silico Screening of Available Drugs Targeting Non-Small Cell Lung Cancer Targets: A Drug Repurposing Approach." Pharmaceutics 14, no. 1 (December 28, 2021): 59. http://dx.doi.org/10.3390/pharmaceutics14010059.
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The RAS–RAF–MEK–ERK pathway plays a key role in malevolent cell progression in many tumors. The high structural complexity in the upstream kinases limits the treatment progress. Thus, MEK inhibition is a promising strategy since it is easy to inhibit and is a gatekeeper for the many malignant effects of its downstream effector. Even though MEK inhibitors are under investigation in many cancers, drug resistance continues to be the principal limiting factor to achieving cures in patients with cancer. Hence, we accomplished a high-throughput virtual screening to overcome this bottleneck by the discovery of dual-targeting therapy in cancer treatment. Here, a total of 11,808 DrugBank molecules were assessed through high-throughput virtual screening for their activity against MEK. Further, the Glide docking, MLSF and prime-MM/GBSA methods were implemented to extract the potential lead compounds from the database. Two compounds, DB012661 and DB07642, were outperformed in all the screening analyses. Further, the study results reveal that the lead compounds also have a significant binding capability with the co-target PIM1. Finally, the SIE-based free energy calculation reveals that the binding of compounds was majorly affected by the van der Waals interactions with MEK receptor. Overall, the in silico binding efficacy of these lead compounds against both MEK and PIM1 could be of significant therapeutic interest to overcome drug resistance in the near future.
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Han, Hyun-Ju, and Chang-Gu Hyun. "Acenocoumarol Exerts Anti-Inflammatory Activity via the Suppression of NF-κB and MAPK Pathways in RAW 264.7 Cells." Molecules 28, no. 5 (February 22, 2023): 2075. http://dx.doi.org/10.3390/molecules28052075.
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The repurposing of already-approved drugs has emerged as an alternative strategy to rapidly identify effective, safe, and conveniently available new therapeutic indications against human diseases. The current study aimed to assess the repurposing of the anticoagulant drug acenocoumarol for the treatment of chronic inflammatory diseases (e.g., atopic dermatitis and psoriasis) and investigate the potential underlying mechanisms. For this purpose, we used murine macrophage RAW 264.7 as a model in experiments aimed at investigating the anti-inflammatory effects of acenocoumarol in inhibiting the production of pro-inflammatory mediators and cytokines. We demonstrate that acenocoumarol significantly decreases nitric oxide (NO), prostaglandin (PG)E2, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β levels in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Acenocoumarol also inhibits the expression of NO synthase (iNOS) and cyclooxygenase (COX)-2, potentially explaining the acenocoumarol-induced decrease in NO and PGE2 production. In addition, acenocoumarol inhibits the phosphorylation of mitogen-activated protein kinases (MAPKs), c-Jun N terminal kinase (JNK), p38 MAPK, and extracellular signal-regulated kinase (ERK), in addition to decreasing the subsequent nuclear translocation of nuclear factor κB (NF-κB). This indicates that acenocoumarol attenuates the macrophage secretion of TNF-α, IL-6, IL-1β, and NO, inducing iNOS and COX-2 expression via the inhibition of the NF-κB and MAPK signaling pathways. In conclusion, our results demonstrate that acenocoumarol can effectively attenuate the activation of macrophages, suggesting that acenocoumarol is a potential candidate for drug repurposing as an anti-inflammatory agent.
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R. Sahrawat, Tammanna, and Prabhjeet Kaur Kaur. "Polypharmacological study of Ceritinib using a structure based in silico approach." Bionatura 4, no. 2 (May 15, 2019): 836–40. http://dx.doi.org/10.21931/rb/2019.04.02.3.
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Drug repurposing has gained mass recognition over the past few years as it has paved new therapeutic applications for already approved FDA drugs. It focuses on finding new molecular targets of drugs for medical uses different than the one originally proposed. Ceritinib, an Anaplastic Lymphoma Kinase (ALK) inhibitor is given orally in the treatment of non-small cell lung cancer (NSCLC). This treatment has been reported to be associated with a number of side effects such as hyperglycemia, convulsion, pneumonitis etc. The side effects are usually due to the unintended interaction of the drug with other protein targets. In silico polypharmacological studies of Ceritinib suggests that it binds to multiple targets other than the intended one which may largely be due to different proteins possessing similar binding sites. ProBis server was used to retrieve probable off-targets of Ceritinib based on presence of structurally similar protein binding sites as that of ALK. Ceritinib was found to bind effectively to three proteins namely Lymphocyte Cell-Specific Protein-Tyrosine Kinase, Tropomyosin receptor kinase B and Aurora kinase B having favorable binding energies and inhibition constants, with no reported side-effects as compared to their marketed drugs. Therefore, it is concluded from the present study that Ceritinib may act as an effective therapeutic target against its polypharmacological targets.
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Brunotte, Linda, Shuyu Zheng, Angeles Mecate-Zambrano, Jing Tang, Stephan Ludwig, Ursula Rescher, and Sebastian Schloer. "Combination Therapy with Fluoxetine and the Nucleoside Analog GS-441524 Exerts Synergistic Antiviral Effects against Different SARS-CoV-2 Variants In Vitro." Pharmaceutics 13, no. 9 (September 3, 2021): 1400. http://dx.doi.org/10.3390/pharmaceutics13091400.
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The ongoing SARS-CoV-2 pandemic requires efficient and safe antiviral treatment strategies. Drug repurposing represents a fast and low-cost approach to the development of new medical treatment options. The direct antiviral agent remdesivir has been reported to exert antiviral activity against SARS-CoV-2. Whereas remdesivir only has a very short half-life time and a bioactivation, which relies on pro-drug activating enzymes, its plasma metabolite GS-441524 can be activated through various kinases including the adenosine kinase (ADK) that is moderately expressed in all tissues. The pharmacokinetics of GS-441524 argue for a suitable antiviral drug that can be given to patients with COVID-19. Here, we analyzed the antiviral property of a combined treatment with the remdesivir metabolite GS-441524 and the antidepressant fluoxetine in a polarized Calu-3 cell culture model against SARS-CoV-2. The combined treatment with GS-441524 and fluoxetine were well-tolerated and displayed synergistic antiviral effects against three circulating SARS-CoV-2 variants in vitro in the commonly used reference models for drug interaction. Thus, combinatory treatment with the virus-targeting GS-441524 and the host-directed drug fluoxetine might offer a suitable therapeutic treatment option for SARS-CoV-2 infections.
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Elkamhawy, Ahmed, Usama M. Ammar, Sora Paik, Magda H. Abdellattif, Mohamed H. Elsherbeny, Kyeong Lee, and Eun Joo Roh. "Scaffold Repurposing of In-House Small Molecule Candidates Leads to Discovery of First-in-Class CDK-1/HER-2 Dual Inhibitors: In Vitro and In Silico Screening." Molecules 26, no. 17 (September 1, 2021): 5324. http://dx.doi.org/10.3390/molecules26175324.
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Recently, multitargeted drugs are considered a potential approach in treating cancer. In this study, twelve in-house indole-based derivatives were preliminary evaluated for their inhibitory activities over VEGFR-2, CDK-1/cyclin B and HER-2. Compound 15l showed the most inhibitory activities among the tested derivatives over CDK-1/cyclin B and HER-2. Compound 15l was tested for its selectivity in a small kinase panel. It showed dual selectivity for CDK-1/cyclin B and HER-2. Moreover, in vitro cytotoxicity assay was assessed for the selected series against nine NCI cell lines. Compound 15l showed the most potent inhibitory activities among the tested compounds. A deep in silico molecular docking study was conducted for compound 15l to identify the possible binding modes into CDK-1/cyclin B and HER-2. The docking results revealed that compound 15l displayed interesting binding modes with the key amino acids in the binding sites of both kinases. In vitro and in silico studies demonstrate the indole-based derivative 15l as a selective dual CDK-1 and HER-2 inhibitor. This emphasizes a new challenge in drug development strategies and signals a significant milestone for further structural and molecular optimization of these indole-based derivatives in order to achieve a drug-like property.
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Meijer, Laurent, Deborah J. Nelson, Vladimir Riazanski, Aida G. Gabdoulkhakova, Geneviève Hery-Arnaud, Rozenn Le Berre, Nadège Loaëc, et al. "Modulating Innate and Adaptive Immunity by (R)-Roscovitine: Potential Therapeutic Opportunity in Cystic Fibrosis." Journal of Innate Immunity 8, no. 4 (2016): 330–49. http://dx.doi.org/10.1159/000444256.
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(R)-Roscovitine, a pharmacological inhibitor of kinases, is currently in phase II clinical trial as a drug candidate for the treatment of cancers, Cushing's disease and rheumatoid arthritis. We here review the data that support the investigation of (R)-roscovitine as a potential therapeutic agent for the treatment of cystic fibrosis (CF). (R)-Roscovitine displays four independent properties that may favorably combine against CF: (1) it partially protects F508del-CFTR from proteolytic degradation and favors its trafficking to the plasma membrane; (2) by increasing membrane targeting of the TRPC6 ion channel, it rescues acidification in phagolysosomes of CF alveolar macrophages (which show abnormally high pH) and consequently restores their bactericidal activity; (3) its effects on neutrophils (induction of apoptosis), eosinophils (inhibition of degranulation/induction of apoptosis) and lymphocytes (modification of the Th17/Treg balance in favor of the differentiation of anti-inflammatory lymphocytes and reduced production of various interleukins, notably IL-17A) contribute to the resolution of inflammation and restoration of innate immunity, and (4) roscovitine displays analgesic properties in animal pain models. The fact that (R)-roscovitine has undergone extensive preclinical safety/pharmacology studies, and phase I and II clinical trials in cancer patients, encourages its repurposing as a CF drug candidate.
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Maxson, Julia Elizabeth, Abel L. Melissa, Jinhua Wang, Xianming Deng, Samuel B. Luty, Huahang Sun, Julie Gorenstein, et al. "Development and Repurposing of Small-Molecule Kinase Inhibitors to Target Novel Leukemogenic TNK2 Mutations." Blood 124, no. 21 (December 6, 2014): 435. http://dx.doi.org/10.1182/blood.v124.21.435.435.
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Abstract BACKGROUND: A tremendous amount of information now exists detailing the genetic alterations present in leukemia cells. However, our understanding of the functional significance of many of these genetic events remains incomplete. One major challenge involves the identification of pharmacologically targetable mutations for the design and implementation of targeted therapy strategies. To this end, we are using an algorithm called HitWalker (Bottomly, et al. 2013), which can prioritize gene mutations based on functional data, thus revealing the pharmacologic vulnerabilities of leukemia cells from individual patients. This analysis revealed oncogenic mutations in the tyrosine kinase, TNK2 (aka ACK1), which can be targeted with existing small-molecule inhibitors. METHODS: Kinase inhibitor screens were run on primary patient samples, and the operationally important kinases underlying drug sensitivity patterns were predicted based on an algorithm that harnesses the known efficacy of each drug against the kinome (algorithm described in Tyner, et al. 2013). The results of the drug screens were integrated with high throughput sequencing data using the HitWalker algorithm such that mutated genes were ranked according to closest associations with kinases implicated by the functional screening data. Oncogenicity of TNK2 mutations was tested by Ba/F3 cytokine independent growth assays. To develop TNK2 inhibitors, we searched our in-house database for inhibitors that exhibited potent and selective binding to TNK2. The kinase selectivity of the compounds was evaluated by screening against a diverse panel of 241 kinases using a chemical proteomic approach, KiNativ. RESULTS: The integrated functional genomic analysis revealed TNK2 mutations in AML and CMML leukemia samples, which ranked highly as potential therapeutic targets. The TNK2 point mutations exhibited transformative capacity, and transformed cells exhibited sensitivity to the multi-kinase inhibitor dasatinib, which antagonizes TNK2 kinase activity. In addition, we observed sensitivity to novel TNK2 inhibitors, XMD8-87 and XMD16-5, which possess greater specificity for TNK2. XMD8-87 in particular demonstrated a high degree of selectivity for TNK2, and is more potent than the previously reported TNK2 inhibitor, AIM-100. CONCLUSION: Here we prioritized TNK2 mutations as important functional targets using the HitWalker algorithm. This highlights the utility of integrating functional and genomic data to identify actionable genetic lesions. Given the large number of mutations present in a wide variety of tumors, the ability to prioritize genetic lesions greatly reduces the time and resources necessary to validate candidate mutations. Furthermore, this study highlights the utility of drug screening data for understanding the underlying vulnerabilities of leukemia cells and their accompanying gene mutations. In addition, we newly describe two kinase inhibitors that exhibit greater selectivity for TNK2 compared with dasatinib. These compounds represent exciting new lead candidates for further development of clinically applicable, selective TNK2 inhibitors. Disclosures Druker: Bristol-Myers Squibb: Clinical trial funding: PI and co-investigator on BMS clinical trials. OHSU has contracts with BMS to pay for patient costs, nurse and data manager salaries, and institutional overhead. I do not derive salary, or lab funds from these contracts. Clinical trial funding: PI and co-investigator on BMS clinical trials. OHSU has contracts with BMS to pay for patient costs, nurse and data manager salaries, and institutional overhead. I do not derive salary, or lab funds from these contracts. Other; ARIAD: Clinical trial funding: PI and co-investigator on ARIAD clinical trials. OHSU has contracts with ARIAD to pay for patient costs, nurse and data manager salaries, and institutional overhead. I do not derive salary, or lab funds from these contracts. Other; Novartis: Clinical trial funding: PI and co-investigator on Novartis clinical trials. OHSU has contracts with Novartis to pay for patient costs, nurse and data manager salaries, and institutional overhead. I do not derive salary, or lab funds from these contracts. Clinical trial funding: PI and co-investigator on Novartis clinical trials. OHSU has contracts with Novartis to pay for patient costs, nurse and data manager salaries, and institutional overhead. I do not derive salary, or lab funds from these contracts. Other, Dr. Druker is the inventor of a technology that is licensed to Novartis. This financial conflict of interest has been reviewed and managed by OHSU. Patents & Royalties; MolecularMD: Consultancy, Equity Ownership, Scientific Founder, Scientific Founder. Some clinical trials on which I participate as PI or co-investigator utilize MolecularMD for molecular testing. This potential individual and institutional conflict of interest has been reviewed and managed by OHSU. Other; Lorus Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Stock options Other; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; D3: Consultancy; Cylene Pharmaceuticals: Consultancy, Equity Ownership; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Scientific Founder, Scientific Founder Other; CTI Biopharma: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Consultancy; Millipore: Dr. Druker is the inventor of a technology that is licensed to Millipore. This financial conflict of interest has been reviewed and managed by OHSU Patents & Royalties; Misc other pharmaceutical companies: Dr. Druker is an inventor on OHSU patent #843, licensed to many companies including but not limited to ARIAD; Array BioPharma; Curis; MolecularMD; Pfizer; Piramal Health Care; Praecis; SGX; The Translational Genomics Research Institute; and Vertex. Patents & Royalties. Tyner:Incyte: Research Funding.
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Chen, Ya-Ping, Hui-Ju Lin, Kung-Chao Chang, Jiann-Shiuh Chen, Ming-Ying Tsai, Liang-Yi Hung, and Tsai-Yun Chen. "Targeting Aurora Kinases in Acute Lymphoblastic Leukemia." Blood 120, no. 21 (November 16, 2012): 4907. http://dx.doi.org/10.1182/blood.v120.21.4907.4907.
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Abstract Abstract 4907 Introduction: Despite improved treatment outcome in acute lymphoblastic leukemia (ALL), drug resistance and disease recurrence remain major obstacles in specific subgroups. Thus, there is an urgent need to identify new targets for therapy. Several studies showed that Aurora kinases were therapeutic targets in cancer therapy, including solid tumors and hematological malignancies. Here we describe preclinical testing of Aurora kinase inhibitors in ALL and the molecular mechanism of different drug activity. Materials and methods: Quantitative RT-PCR and Western blot were used to assess the expressions of Aurora kinases and their activators in ALL. RT-PCR was used to detect the expression of MDR-1. To test activity against Aurora kinases, different ALL cell lines were treated with various concentrations of Aurora kinase inhibitors “VE-465 and VX-680”. The effects of Aurora kinase inhibitors on the cell cycle were evaluated by flow cytometry. Gene expression profiling was performed to identify the candidate targets which regulate the different drug sensitivity. Transient knockdown and overexpression of candidate genes in ALL cell lines were also employed in this study. Results: Nine ALL cell lines treated with Aurora kinase inhibitors (VE-465 and VX-680) exhibited different drug sensitivity. Five ALL cell lines were sensitive to drug treatment with IC50 around 10–40 nM, including MLL-AF4-positive and BCR-ABL-positive cell lines. However, RPMI-8402 was one of the three cell lines which were resistant to VE-465 and VX-680 with IC50 more than 10 μM. Among these sensitive ALL cell lines, treatment of Aurora kinase inhibitors resulted in an increased G2/M and sub-G1 populations. In contrast, drug-resistant ALL cell lines showed increased polyploidy status after exposure to Aurora kinase inhibitors. The different treatment efficacy was not related to the expression of Aurora kinases, their activators or MDR-1. In order to elucidate the molecular mechanism to regulate the different drug sensitivity, microarray study was performed. It showed that treatment of Aurora kinase inhibitors resulted in differential expressions of genes (75 up-regulated and 90 down-regulated genes) and CDKN1Awas one of the potential molecules which regulated the treatment diversity. RT-PCR and Western blot confirmed the cDNA microarray data: CDKN1A was up-regulated after treatment with Aurora kinase inhibitors in the drug-sensitive cell lines, but no change in the level of CDKN1A in the drug-resistance cell lines. Knockdown of CDKN1A in drug-sensitive cell lines impaired the treatment activity. Over-expression of CDKN1A in drug-resistant cell lines increased the anti-leukemia effect of Aurora kinase inhibitors. Conclusion: These data suggest that treatment with Aurora kinase inhibitors may be a novel and effective therapy in specific subgroups of ALL, including MLL-AF4-positive ALL. These data show that status of Aurora kinases, their activators or MDR-1 does not correlate with the drug susceptibility in ALL cell lines. The susceptibility to Aurora kinase inhibitors in ALL depends on the activation status of CDKN1A. Disclosures: No relevant conflicts of interest to declare.
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Maney, N., H. De Paula-Lemos, B. Barron-Millar, A. Mellor, J. D. Isaacs, A. Anderson, and A. Pratt. "SAT0013 PIM-1 KINASE IS A MEASURABLE MEDIATOR OF CD4+ T CELL DYSREGULATION AND THERAPEUTIC TARGET IN EARLY RHEUMATOID ARTHRITIS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 936.1–937. http://dx.doi.org/10.1136/annrheumdis-2020-eular.2818.
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Background:As well as being an established oncoprotein and a therapeutic target in cancer,Proviral Integration site for murine Moloney leukemia virus-1(pim-1) has been implicated in human autoimmunity. We previously confirmed this serine-threonine protein kinase to be strikingly upregulated in circulating CD4+ T cells of untreated rheumatoid arthritis (RA) patients as a consequence of IL-6 signalling1-2. Evidence for the relevance of pim-1 signalling in the disruption of RA synovial fibroblast (RASF) homeostasis3further supports its candidacy as a therapeutic target.Objectives:To investigate PIM1 and its family members (PIM2 and PIM3) as potential candidates for drug repurposing in RA.Methods:A flow cytometric assay for PIM1 transcript measurement in circulating CD4+ T cells of early arthritis patients was validated against real-time PCR in paired cells isolated by bead selection. Synovial protein expression in tissue from the same cohort of untreated RA patients and disease controls was determined by quantitative multiplex immunofluorescence. The functional consequences of manipulating pim kinase family expression in freshly purified T cell receptor (TCR)-stimulated CD4+ T cells from early RA patients was explored. The impact of pim-1 specific and pim-1-3 (pan-pim) kinase inhibition on progression of the IL-6 dependent collagen-induced arthritis (CIA) model was assessed.Results:The percentage of circulating CD4+ T cells positive forPIM1transcript by flow cytometry proved a faithful surrogate for gene expression in early arthritis (Figure 1A), distinguishing RA from other pathologies (Figure 1B). Pim-1 protein expression was increased in the synovium of untreated RA compared with disease controls, including amongst infiltrating CD4+ T cells (Figure 1C-D).In vitro, exposure of TCR-stimulated early RA CD4+ T cells to pim kinase inhibitors restrained their activation and proliferative capacity; diminished pro-inflammatory cytokine production (IFN-g and IL-17) and an expanded CD25hiFoxP3+ regulatory T cell (Treg) fraction were also observed in treatedversusun-treated cells. Finally, administration of pim inhibitors robustly attenuated clinical scores of arthritis in the CIA model, with reduced cartilage loss observed in animals treated with a pan-PIM inhibitor compared with vehicle control (Figure 2).Conclusion:Our data highlight pim kinases as plausible therapeutic targets for a subgroup of early RA patients that may be identifiable using tractable in vitro assays. Pim kinase inhibitors could simultaneously target immune inflammation and RASF dysregulation; consideration should now be given to their repurposing for this condition.References:[1] Anderson AE et al Annals of the Rheumatic Diseases 2016; 75:466-73.[2] Anderson AE et al Rheumatology 2019; 58:1250-1258[3] Ha YJ et al Rheumatology 2019; 58:154-64Disclosure of Interests:Nicola Maney Consultant of: Current employee of Eli Lilly, Henrique De Paula-Lemos: None declared, Ben Barron-Millar: None declared, Andrew Mellor Shareholder of: NewLink Genetics PLC, and has received patent licensing income from this source., John D Isaacs Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Gilead, Janssen, Merck, Pfizer, Roche, Amy Anderson: None declared, Arthur Pratt Grant/research support from: Pfizer, GlaxoSmithKlein
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Moore, Andrew S., Amir Faisal, Vassilios Bavetsias, Chongbo Sun, Butrus Atrash, Melanie Valenti, Alexis de Haven Brandon, et al. "Dual Inhibition of Aurora and FLT3 Kinases by CCT137690: A Novel Treatment Strategy Against FLT3-ITD Positive AML In Vitro and In Vivo." Blood 116, no. 21 (November 19, 2010): 3289. http://dx.doi.org/10.1182/blood.v116.21.3289.3289.
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Abstract Abstract 3289 The Aurora kinases are a family of serine-threonine kinases that play key roles in different stages of mitosis. Over-expression of Aurora kinases has been demonstrated in a range of malignancies including leukemia. Aurora kinase inhibitors are emerging as promising agents in the treatment of acute myeloid leukemia (AML) with a number of compounds currently being assessed in clinical trials (Moore AS et al, Leukemia 2010). CCT137690, an imidazo[4,5-b]pyridine derivative discovered at our Institute, is an orally bioavailable, potent, pan-Aurora and FLT3 inhibitor with low nanomolar IC50 values against Aurora A (15 nM), Aurora B (25 nM), Aurora C (19 nM), and FLT3 (<0.5 nM) kinases. CCT137690 showed in vitro and in vivo activity in human colon cancer cell lines and xenograft models (Bavetsias V et al, J Med Chem 2010). Here we report the in vitro and in vivo activity of CCT137690 in FLT3-ITD positive AML. In vitro, the FLT3-ITD positive cell lines MV-4-11 and MOLM-13 are particularly sensitive with GI50 values less than 50 nM. Cellular assays demonstrate that CCT137690 inhibits autophosphorylation of Aurora A, Aurora B and Aurora C kinases and phosphorylation of histone H3, a direct target of Aurora B kinase. CCT137690 also inhibits autophosphorylation of FLT3 and phosphorylation of its downstream targets STAT5 and p44/42 MAPK (Erk1/2). Dual inhibition of Aurora and FLT3 kinases in FLT3-ITD positive AML with CCT137690 induces apoptosis and results in a unique cell cycle profile with cells accumulating in G2/M, whilst selective FLT3 inhibition with MLN518 resulted in G1/S arrest. When given orally to athymic mice, CCT137690 achieved target modulation and potently inhibited the growth of subcutaneous MOLM-13 xenografts, with no obvious toxicity or loss of body weight. Inhibition of MOLM-13 xenograft growth was more pronounced with CCT137690 compared to the selective FLT3 inhibitor MLN518, suggesting that dual inhibition of Aurora and FLT3 kinases may have advantages compared to selective FLT3 inhibition alone. The potent preclinical activity of CCT137690 in FLT3-ITD positive AML models supports the growing body of evidence that dual pan-Aurora and FLT3 kinase inhibitors may be of benefit in the high-risk group of patients with FLT3-ITD positive AML. Disclosures: Moore: The Institute of Cancer Research: Employment, The Institute of Cancer Research (ICR) has a commercial interest in drug development programs. Authors employed by ICR are subject to a Rewards to Inventors Scheme, which may reward contributors to a program that is subsequently licensed. Faisal:The Institute of Cancer Research: Employment. Bavetsias:The Institute of Cancer Research: Employment. Sun:The Institute of Cancer Research: Employment. Atrash:The Institute of Cancer Research: Employment. Valenti:The Institute of Cancer Research: Employment. de Haven Brandon:The Institute of Cancer Research: Employment. Avery:The Institute of Cancer Research: Employment. Raynaud:The Institute of Cancer Research: Employment. Workman:The Institute of Cancer Research: Employment. Pearson:The Institute of Cancer Research: Employment. Blagg:The Institute of Cancer Research: Employment. Eccles:The Institute of Cancer Research: Employment. Linardopoulos:The Institute of Cancer Research: Employment.
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Reiman, Tony, Robert P. Evans, Claudia Naber, Tara Steffler, Jonathan J. Keats, Troy Perry, Christopher A. Maxwell, Heidi Chau, Andrew R. Belch, and Linda M. Pilarski. "Aurora Kinases as Therapeutic Targets in Multiple Myeloma." Blood 108, no. 11 (November 16, 2006): 847. http://dx.doi.org/10.1182/blood.v108.11.847.847.
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Abstract BACKGROUND: We have previously found that in multiple myeloma there is amplification of the centrosome, the organelle that nucleates the mitotic spindle. We have reported that RHAMM is a component of the centrosome which interacts with TPX2, the protein that targets Aurora A kinase to the mitotic spindle. We have also shown that RHAMM expression and alternative splicing in myeloma correlate with centrosome amplification, aggressive disease and poor survival. These findings led us to speculate that Aurora A and possibly other Aurora kinases are potential therapeutic targets in myeloma. METHODS: We examined the expression of Aurora A, B and C kinases in 5 myeloma cell lines and autoMACS-purified CD138+ myeloma bone marrow plasma cells from 20 patients. We assessed the anti-proliferative and pro-apoptotic effects of Aurora A knockdown in myeloma cell lines with RNA interference. We investigated the anti-myeloma activity of two potent, selective Aurora kinase inhibitors, VE-465 (Merck/Vertex) and AZD1152 (AstraZeneca), in 5 myeloma cell lines, in CD138+ bone marrow plasma cells from 2 myeloma patients, and in a NOD/SCID murine xenograft model. RESULTS: Aurora A, B and C kinases are ubiquitously expressed in both myeloma cell lines and myeloma bone marrow plasma cells. Expression levels vary among patients. Aurora A and B are expressed in myeloma plasma cells at levels comparable to that seen in the CD138- cells from the same marrow sample, and comparable to the levels seen in normal marrow from control individuals. Aurora C, while expressed at low levels, is consistently ectopically overexpressed in myeloma plasma cells relative to coexisting CD138- cells and normal marrow. In myeloma cell lines, Aurora A knockdown with RNA interference induces apoptosis and cell killing. In all five myeloma cell lines tested, and in myeloma bone marrow plasma cells from two patients, both VE-465 and AZD1152 induce apoptosis and myeloma cell killing at nanomolar concentrations, to varying degrees (20–80% reduction in cell viability). VE-465 is known to inhibit all three Aurora kinases with comparable specificity, while AZD1152 is known to inhibit Aurora B and C more selectively than Aurora A. Despite these differences in activity, both compounds have comparable pre-clinical efficacy against myeloma. Myeloma cell lines treated with either agent demonstrate a phenotype consistent with target inhibition. Both drugs show additive effects on killing of cell lines and primary myeloma cells when combined with dexamethasone, even in dexamethasone-resistant cells. Anti-myeloma activity was seen with single agent Aurora kinase inhibition in the murine model, at well tolerated doses. CONCLUSIONS: Aurora kinases are potential therapeutic targets in myeloma. Aurora kinase inhibitors comprise an emerging class of anti-cancer drug therapy that deserves further evaluation for myeloma patients.
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Besse, Lenka, Andrej Besse, Marianne Kraus, Matej Jasik, Ondrej Slaby, and Christoph Driessen. "Abstract 2851: ALK-inhibitors as a novel potential therapy for proteasome inhibitor-resistant multiple myeloma." Cancer Research 83, no. 7_Supplement (April 4, 2023): 2851. http://dx.doi.org/10.1158/1538-7445.am2023-2851.
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Abstract Background: Proteasome inhibitors (PI) disrupt the equilibrium between production and disposal of excess and/or misfolded proteins in multiple myeloma (MM) cells, leading to apoptosis. Resistance to PI bortezomib (BTZ) and carfilzomib (CFZ) is a major obstacle to the successful treatment of MM. The drug repurposing approach offers a promising strategy to classical drug development in particular in MM. Previously, ALK-inhibitors were shown to have anti-MM activity ex vivo. Therefore, we aimed to identify the mechanism of action of ALK-inhibitors against MM cells and to identify promising drug therapy combinations of ALK-inhibitors for refractory MM. Methods: A set of PI-naïve and PI-resistant cells was used in the study. Viability of the cells was determined by CCK8 viability assay. Genome-wide CRISPR/Cas9-based loss-of-function screening with Brunello library was used in MM AMO-1 cell line to identify mechanism of action of ceritinib. Western blot was used to assess levels of total and phosphorylated proteins. RNA-seq was used to determine the amount of transcripts in PI-sensitive and PI-resistant cells. Results: Initially, 7 different ALK-inhibitors were tested across PI-naïve and PI-adapted MM cell lines. Based on the IC50 values, the most effective ALK-inhibitors to induce cytotoxicity in MM were ceritinib > brigatinib > crizotinib > entrectinib. The combination of ceritinib, brigatinib and entrectinib showed synergistic cytotoxicity with the PI BTZ and CFZ and overcame PI-resistance in 4 different sets of PI-adapted cells. The strongest synergistic cytotoxicity was observed between ceritinib and CFZ in CFZ-adapted cells. CRISPR/Cas9-screening identified genes involved in negative regulation of mTORC signalling (NPRL2, NPRL3, TSC1, TSC2) and transcription factor FOXO1 as the major resistance candidates to ceritinib. Subsequently, ceritinib treatment significantly inhibited mTORC signaling, suggesting a shut-down of cellular proliferation due to targeting of the upstream receptor-tyrosine kinases (RTK), essential for cell viability and thus not identified by the screening. Further search identified InsR and IGF1R as the overlapping RTK inhibited by ceritinib and brigatinib. Co-treatment of PI-resistant cells with the combination of InsR/IGF1R inhibitors and CFZ induced strong synergistic cytotoxicity, resembling the synergistic cytotoxicity observed for ceritinib and CFZ, whereas InsR/IGF1R inhibitors did not show any synergistic cytotoxicity with ceritinib, suggesting targeting the same pathway. Our data further show that PI-naïve and resistant cells are negative for ALK, but positive for InsR and IGF1R expression. Conclusion: Crizotinib inhibits InsR/IGF1R signaling in MM, which is essential for MM survival and together with CFZ it overcomes PI-resistance. Therefore, it represents a promising and already available therapy for PI-resistant MM patients. Citation Format: Lenka Besse, Andrej Besse, Marianne Kraus, Matej Jasik, Ondrej Slaby, Christoph Driessen. ALK-inhibitors as a novel potential therapy for proteasome inhibitor-resistant multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2851.
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Pollard, John R., Peter A. Charlton, Graham M. T. Cheetham, Susanna C. Falcon, Julian M. C. Golec, Matthew R. Griffiths, and Peter Weber. "Structural Basis and Cellular Consequences of Potent Inhibition of the Aurora Kinases, Wild Type Abl Kinase and a T315I Multi-Drug Resistant Mutant Form of Abl Kinase by MK-0457 (VX-680)." Blood 108, no. 11 (November 16, 2006): 1368. http://dx.doi.org/10.1182/blood.v108.11.1368.1368.
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Abstract MK-0457 (VX-680) is a potent small molecule inhibitor of the Aurora-family of protein kinases that inhibits cell proliferation through aberrant mitosis and failed cytokinesis. Affected cells are subsequently deleted by apoptosis. Tumor regression and increased survival have been reported in multiple in-vivo models and in January 2005 MK-0457 entered Phase I clinical trials as the first in class Aurora inhibitor. Although MK-0457 demonstrates significant selectivity over the vast majority of kinases tested, it has been shown to potently inhibit Flt-3 and Abl, both of which are targets for anti-cancer therapies. Most notably MK-0457 potently inhibits a series of mutant Abl kinases including the multi-drug resistant T315I form that is commonly expressed in Gleevec refractory CML and ALL. We report here the first MK-0457 / Aurora co-complex crystal structure and show that it adopts a closed inactive conformation. By comparison with other reported kinase structures we provide a structural basis for the cross-reactivity with wild type and drug resistant mutants of the Abl kinase. We also show that MK-0457 blocks both Aurora and Abl cellular kinase activity and displays potent cytotoxic activity against a range of leukemic cell lines, including Gleevec resistant cells that are reliant on mutant Abl for growth and survival. Similar observations have recently been made in the clinic, where new data show that MK-0457 has activity in patients with BCR-ABL T315I mutant CML and Philadelphia positive ALL.
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Karatas, Mehmet, Apirat Chaikuad, Bianca Berger, Michael H. G. Kubbutat, Frank Totzke, Stefan Knapp, and Conrad Kunick. "7-(2-Anilinopyrimidin-4-yl)-1-benzazepin-2-ones Designed by a “Cut and Glue” Strategy Are Dual Aurora A/VEGF-R Kinase Inhibitors." Molecules 26, no. 6 (March 14, 2021): 1611. http://dx.doi.org/10.3390/molecules26061611.
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Although overexpression and hyperactivity of protein kinases are causative for a wide range of human cancers, protein kinase inhibitors currently approved as cancer drugs address only a limited number of these enzymes. To identify new chemotypes addressing alternative protein kinases, the basic structure of a known PLK1/VEGF-R2 inhibitor class was formally dissected and reassembled. The resulting 7-(2-anilinopyrimidin-4-yl)-1-benzazepin-2-ones were synthesized and proved to be dual inhibitors of Aurora A kinase and VEGF receptor kinases. Crystal structures of two representatives of the new chemotype in complex with Aurora A showed the ligand orientation in the ATP binding pocket and provided the basis for rational structural modifications. Congeners with attached sulfamide substituents retained Aurora A inhibitory activity. In vitro screening of two members of the new kinase inhibitor family against the cancer cell line panel of the National Cancer Institute (NCI) showed antiproliferative activity in the single-digit micromolar concentration range in the majority of the cell lines.
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Okabe, Seiichi, Tetsuzo Tauchi, Seiichiro Katagiri, Yuko Tanaka, and Kazuma Ohyashiki. "Activity of the Aurora Kinase Inhibitor, MLN8237 (alisertib) Alone or in Combination with Ponatinib Against Imatinib-Resistant BCR-ABL-Positive Cells." Blood 120, no. 21 (November 16, 2012): 1333. http://dx.doi.org/10.1182/blood.v120.21.1333.1333.
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Abstract Abstract 1333 Chronic myeloid leukemia (CML) is characterized by cytogenetic aberration (Philadelphia chromosome: Ph) and chimeric tyrosine kinase BCR-ABL. ABL tyrosine kinase inhibitor, imatinib has demonstrated the potency against CML patients. However, resistance to imatinib can develop in CML patients due to BCR-ABL point mutations. One of T315I mutation is resistant to currently available ABL tyrosine kinase inhibitors. Therefore, new approach against T315I mutant may improve the outcome of Ph-positive leukemia patients. Aurora kinases are serine/threonine kinases and upregulated in many malignancies including leukemia, and play an important role in cell cycle control and tumor proliferations. Because Aurora kinases are overexpressed in leukemia cells, Aurora kinases may present attractive targets for leukemia treatment. One of Aurora kinase inhibitor, MLN8237 (alisertib) is an oral and selective Aurora kinase A inhibitor and is currently being investigated in a pivotal phase 3 clinical trial against hematological malignancies. We suggested that alisertib mediated inhibition Aurora kinase activity and in combination with ponatinib, also known as AP24534 may abrogate the proliferation and survival of Ph-positive cells including T315I mutation. In this study, we investigated the combination therapy with a ponatinib and an alisertib by using the BCR-ABL positive cell line, K562, murine Ba/F3 cell line which was transfected with T315I mutant, ponatinib resistant Ba/F3 cells and T315I primary sample. Protein expression of Aurora A and B were increased in Ph-positive leukemia cells. 72 hours treatment of alisertib exhibits cell growth inhibition and induced apoptosis against K562 cells in a dose dependent manner. Alisertib also induced cell cycle arrest. The treatment of ponatinib exhibits cell growth inhibition partially against K562 cells in the presence of feeder cell (HS-5) conditioned media. We found that the treatment of alisertib abrogated the protective effects of HS-5 conditioned media in K562 cells. We investigated the alisertib activity against T315I positive cells. Alisertib potently induced cell growth inhibition of Ba/F3 cells ectopically expressing T315I mutation and induced cell cycle arrest. We investigated the efficacy between ponatinib and alisertib by using these cell lines. Combined treatment of Ba/F3 T315I cells with ponatinib and alisertib caused significantly more cytotoxicity than each drug alone. Ponatinib and alisertib were also effective against T315I primary samples. We examined the intracellular signaling of alisertib. Phosphorylation of Aurora A was inhibited in a time dependent manner. We also found the phosphorylation of histone H3 was also reduced in a dose dependent manner suggested that high concentration of alisertib also inhibits Aurora B activity. We next investigated by using ponatinib resistant Ba/F3 cells. In the ponatinib resistant cell lines, IC50 of ponatinib was up to 200 nM. BCR-ABL triple point mutations (T315I, E255K and Y253H) were detected by direct sequence analysis. The treatment of alisertib exhibits cell growth inhibition against Ba/F3 ponatinib resistant cells in the dose dependent manner. Alisertib induced cell cycle arrest in ponatinib resistant cells. Combined treatment of Ba/F3 ponatinib resistant cells with ponatinib and alisertib caused significantly more cytotoxicity. To assess the activity of alisertib and ponatinib, we performed to test on CML tumor formation in mice. We injected nude mice subcutaneously with 1×107 Ba/F3 T315I cells. A dose of 30 mg/kg/day p.o of ponatinib and 30 mg/kg/day p.o of alisertib inhibited tumor growth and reduced tumor volume compared with control mice. The treatments were well tolerated with no animal health concerns observed indicating the feasibility of alisertib combination strategies in the clinic. Data from this study suggested that administration of the ponatinib and Aurora inhibitor, alisertib may be a powerful strategy against BCR-ABL mutant cells including T315I. Disclosures: No relevant conflicts of interest to declare.
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Cheung, Kam, Gloria Juan, William Wayne, Kelly Hanestad, Kathleen Keegan, Justin Huard, Patricia McElroy, et al. "AMG 900, a Potent and Highly Selective Aurora Kinase Inhibitor Shows Promising Preclinical Activity Against Acute Myeloid Leukemia Cell Lines In Vitro and In Vivo." Blood 122, no. 21 (November 15, 2013): 3823. http://dx.doi.org/10.1182/blood.v122.21.3823.3823.
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Abstract Aurora kinases A and B play essential roles in multiple stages of mitosis and are frequently overexpressed in a subset of human cancers, including acute myeloid leukemia (AML) (Ikezoe T et al, 2007). AMG 900, a potent and highly selective small molecule inhibitor of aurora kinases, is currently in Phase 1 clinical testing in adult patients with AML. In this study, we report the preclinical effects of AMG 900 in AML cell lines. We show that AMG 900 inhibits the phosphorylation of Histone H3 on serine-10 (a proximal substrate of aurora-B) leading to aborted cell division, apoptosis and/or polyploidy. We evaluated the activity of AMG 900 and two other well-characterized aurora kinase inhibitors [AZD1152-hQPA (B-selective AKI) and MLN8054 (A-selective AKI)] in a panel of AML cell lines. AMG 900 inhibited proliferation in all 10 cell lines at single-digit nanomolar concentrations. At effective concentrations, AMG 900 and AZD1152-hQPA showed similar cellular phenotypes, indicating that the activity of AMG 900 may occur through inhibition of aurora-B. A subset of cell lines sensitive to AMG 900 and MLN8054 were insensitive to AZD1152-hQPA, suggesting that AMG 900 may be less susceptible to resistance mediated by drug-efflux (Grundy M et al, 2011). Two AMG 900 oral dosing schedules are being evaluated in the ongoing AML clinical trial; patients receive either 4 or 7 consecutive daily doses followed by a drug holiday in 14-day cycles. In this study, we evaluated the in vivo anti-proliferative effects of AMG 900 using the two dose schedules in the skeleton of NOD/SCID IL2γnull mice bearing MOLM-13 (AML) cells expressing luciferase. To assess tumor cell proliferation in vivo, we used 18FLT (radioactive thymidine analog) PET/CT imaging, a technique that has been used to monitor early treatment response in the bone marrow of AML patients (Vanderhoek M et al, 2011). Mice were imaged for luciferase activity and 18FLT uptake before treatment and at multiple time-points during the drug holiday phase within the 14-day cycle. While the two AMG 900 dosing schedules resulted in a similar decrease in tumor burden across study time points (as measured by luciferase activity), they differed in the timing of skeletal 18FLT responses. Mice administered AMG 900 showed an attenuated skeletal 18FLT uptake compared with the vehicle group, followed by an 18FLT flare. This 18FLT flare event is notably higher using the AMG 900 4-day schedule, although the cumulative dose is similar for both schedules. This difference in 18FLT flaring may indicate the schedules differ in the duration and/or level of target inhibition in the skeletal tumor and bone marrow cells. Mice treated with sunitinib (positive control agent) did not show a skeletal 18FLT flare during the drug holiday, suggesting its mode of action is distinct from that of AMG 900. At the end of the study, mouse bone marrow was assessed for tumor burden by flow cytometry. Mice treated with AMG 900 showed a significant decrease in tumor burden compared with the vehicle group. Interestingly, the mice administered AMG 900 7-day schedule showed the most suppression of tumor growth compared with either AMG 900 4-day schedule or sunitinib. Together, our preclinical studies demonstrate that AMG 900 is a potent inhibitor of aurora kinases that robustly suppresses the growth of AML cells in vitro and in vivo. Furthermore, we highlight the utility of in vivo imaging to monitor AMG 900 drug action, which may help to inform future dose scheduling and drug combination studies. Disclosures: Cheung: Amgen Inc: Employment, Equity Ownership. Juan:Amgen Inc.: Employment, Equity Ownership. Wayne:Amgen Inc.: Employment, Equity Ownership. Hanestad:Amgen Inc.: Employment, Equity Ownership. Keegan:Amgen Inc.: Employment, Equity Ownership. Huard:Amgen Inc.: Employment, Equity Ownership. McElroy:Amgen Inc.: Employment, Equity Ownership. Stanton:Amgen Inc.: Employment, Equity Ownership. Bush:Amgen Inc.: Employment, Equity Ownership. Kendall:Amgen Inc.: Employment, Equity Ownership. Radinsky:Amgen Inc.: Employment, Equity Ownership. Abella:Amgen Inc. : Employment, Equity Ownership. Pieslor:Amgen Inc.: Employment, Equity Ownership. Friberg:Amgen Inc.: Employment, Equity Ownership. Coxon:Amgen Inc.: Employment, Equity Ownership. Gamelin:Amgen Inc: Employment, Equity Ownership. Payton:Amgen Inc.: Employment, Equity Ownership. Off Label Use: AMG 900 is currently in phase 1 clinical development, there is no approved label.
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Islam, Saiful, Muhammed H. Rahaman, Mingfeng Yu, Benjamin Noll, Jennifer H. Martin, Shudong Wang, and Richard Head. "Anti-Leukaemic Activity of Rilpivirine Is Mediated by Aurora A Kinase Inhibition." Cancers 15, no. 4 (February 7, 2023): 1044. http://dx.doi.org/10.3390/cancers15041044.
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Acute myeloid leukaemia (AML) affects predominantly elderly people and has an incidence of 1% of all cancers and 2% of all cancer deaths. Despite using intensive chemotherapy and allogeneic stem cell transplantation, the treatment options for AML remain open for innovation. Thus, there is a need to explore alternative therapies such as less toxic targeted therapies in AML. Aurora A kinase is a well-established target for the treatment of various cancers, including AML. This kinase plays a pivotal role in the cell-division cycle, particularly in different stages of mitosis, and is also involved in many other cellular regulatory processes. In a previous study, we demonstrated that the anti-viral drug rilpivirine is an Aurora A kinase inhibitor. In the current study, we have further explored the selectivity of rilpivirine for Aurora A kinase inhibition by testing this drug against a panel of 429 kinases. Concurrently, we demonstrated that rilpivirine significantly inhibited the proliferation of AML cells in a time- and concentration-dependent manner that was preceded by G2/M cell-cycle arrest leading to the induction of apoptosis. Consistent with its kinase inhibitory role, rilpivirine modulated the expression of critical proteins in the Aurora A kinase-signalling pathway. Importantly, orally administered rilpivirine significantly inhibited tumour growth in an HL-60 xenograft model without showing body weight changes or other clinical signs of toxicity. Furthermore, rilpivirine enhanced the anti-proliferative efficacy of the conventional anti-leukaemic chemotherapeutic agent cytarabine. Collectively, these findings provide the stimulus to explore further the anti-leukaemic activity of the anti-viral drug rilpivirine.
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Lunghi, Paolo, Laura Mazzera, Guerino Lombardi, Micaela Ricca, Manuela Abeltino, Davide Arienti, Anna Maria Cantoni, Attilio Corradi, and Antonio Bonati. "Pan-Aurora Kinases and TRAIL Combination Therapy Has Potent Antitumor Activity In Vivo Against Drug-Resistant Human Multiple Myeloma Xenograft Model." Blood 118, no. 21 (November 18, 2011): 1846. http://dx.doi.org/10.1182/blood.v118.21.1846.1846.
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Abstract Abstract 1846 Although novel drugs such as Bortezomib and Thalidomide have extended the overall survival of multiple myeloma patients they often do not achieve lasting cures, providing an impetus to search for novel therapeutic modalities. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL, also known as Apo2L) is a member of the TNF family of death receptor ligands and has significant potential for use in cancer therapy because of its potent ability to selectively kill cancer cells while sparing normal cells. Preclinical studies have demonstrated that combinations with cytotoxic chemotherapy or other targeted agents may enhance the antitumor activity of TRAIL through cross-talk between the intrinsic and extrinsic pathways. We here demonstrate that targeting Aurora A and B kinases with selective pan-Aurora kinases inhibitors (AKIs) (VX-680, Vertex/Merck; or PHA-680632, Nerviano Medical Sciences, Pfizer) strikingly enhances TRAIL-induced cytotoxicity in TRAIL-sensitive and -resistant human myeloma cell lines (HMCLs) via potentiation of both the death receptor-mediated and mitochondrial apoptotic pathways. In particular, we found that co-treatment with pan-AKIs elevated (DR4+DR5)/(DcR1+DcR2) ratio, caspase-8 activation, Bid fragmentation, mitochondrial depolarization and caspase-9 activation of TRAIL-treated HMCLs. Furthermore we found that the combination of pan-AKIs with TRAIL enhanced the levels of the pro-apoptotic protein Bak and reduced the basal and/or TRAIL-induced expression of the anti-apoptotic Bfl-1/A1 and Mcl-1 at the mitochondrial level; notably, loss of either Mcl-1 or Bfl-1/A1 expression greatly increased TRAIL sensitivity in both sensitive and resistant HMCLs analyzed. To assess the in vivo efficacy of combining TRAIL and Pan-AKIs, we tested these compounds using mouse tumor human plasmacytoma xenograft model in which the drug-resistant RPMI 8226/R5 cells (1.0×107 cells per mouse) were injected subcutaneously into NOD-SCID mice. When the tumors reached approximately 250 mm3 mice bearing RPMI 8226/R5 tumors were randomized (n=12/group) to receive vehicle or MK-0457 or PHA-680632 at 50mg/kg or TRAIL (300μg/per mouse) or MK-0457/TRAIL or PHA-680632/TRAIL. Both Pan-AKIs and TRAIL were administered by intraperitoneal injection. Mice were treated with daily doses of Pan-Aurora inhibitors for 9 days, and two doses of TRAIL. Treatment of RPMI 8226/R5 MM-tumor-bearing mice with MK-0457 or PHA-680632 significantly reduced MM-tumor growth as compared to control (P <.01, Tukey-Kramer test), TRAIL had minimal effect on the growth of tumors, which increased as in control mice. Importantly, when Pan-Aurora inhibitors were combined with TRAIL, there was a significant (P<.001 Dunnet test) reduction in tumor growth relative to either treatment alone. Furthermore, the combination pan-AKIs/TRAIL significantly (P<.001; Kaplan-Meier method and compared using the log-rank test, followed by a Bonferroni correction for multiple comparisons) prolonged survival compared with treatment with either drug alone and was well tolerated in vivo. We next investigated the in vivo effects of the drug combination on proliferation and apoptosis; whole tumor-cell tissues and tumor lysates from mice treated for six days (n=3/group) were subjected to immunohistochemical staining and immunoblotting to assess in vivo phosphorylation histone H3 on Ser10 (phospho-H3), a direct downstream target of the Aurora Kinases, cleaved caspase-3 and PARP fragmentation. Tumor tissues from pan-AKIs treatments resulted in profound phospho-Histone H3 inhibition compared with tumor tissues from vehicle control or TRAIL-treated animals thereby confirming the tumors growth retardation observed in pan-AKIs-treated mice. Either pan-AKIs or TRAIL alone slightly increased caspase-3 cleavage/activation and PARP fragmentation compared with tumors from control cohorts. However, the combination pan-AKIs/TRAIL dramatically increased caspase-3 cleavage/activation, PARP degradation in tumors. In conclusion, our preclinical in vitro and in vivo studies provide the framework for testing pan-AKIs and TRAIL combination therapy in clinical trials aimed to improve patient outcome in MM. Disclosures: No relevant conflicts of interest to declare.
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Abdusalam, Ashraf Ahmed Ali. "In-silico identification of novel inhibitors for human Aurora kinase B form the ZINC database using molecular docking-based virtual screening." Research Results in Pharmacology 8, no. 4 (December 15, 2022): 89–99. http://dx.doi.org/10.3897/rrpharmacology.8.82977.
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Introduction: Aurora kinase enzymes play critical functions in mammals. Aurora kinases are mitotic regulators that are involved in a variety of processes during cell division. The overexpression of these enzymes is associated with tumour formation and is symptomatic of clinical circumstances in cancer patients who have been diagnosed. Materials and methods: The current study reports an in-silico virtual screening (VS) and molecular docking analysis of 2500 compounds retrieved from the ZINC database and five current clinical trial compounds against Aurora Kinase B using AutoDock Vina to identify potential inhibitors. Results and discussion: The top six compounds that resulted from the screening were ZINC00190959, ZINC07889110, ZINC0088285, ZINC01404326, ZINC00882846 and ZINC08813187, which showed lower free energy of binding (FEB) against the target protein binding pocket. The FEB were as follows: -11.92, -11.85, -11.46, -11.33, -11.21 and -11.1 kcal/mol, using AutoDock, and -11.7, -11.5, -11.2, -11.0, -10.8 and -10.6 kcal/mol for AutoDock Vina, respectively. These findings were superior to those obtained with the co-crystallized ligand VX-680, with a -7.5 kcal/mol and the current clinical trial drug. Finally, using a VS and molecular docking approach, novel Aurora kinase B inhibitors were effectively identified from the ZINC database fulfilling the Lipinski rule of five with low FEB and functional molecular interactions with the target protein. Conclusion: The findings suggest that the six compounds could be used as a potential agent for cancer treatments. Graphical abstract
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Bhongade, Bhoomendra A., Nikhil D. Amnerkar, and Andanappa K. Gadad. "3D-QSAR Studies on 4,5-Dihydro-1H-pyrazolo [4,3-h] Quinazolines as Plk-1, CDK2/A and Aur-A Serine/Threonine Kinase Inhibitors." Letters in Drug Design & Discovery 17, no. 4 (April 25, 2020): 388–95. http://dx.doi.org/10.2174/1570180816666190611161332.
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Background: The family of serine/threonine protein kinases is associated with peculiar tumor cell-cycle checkpoints which are overexpressed in proliferating tissues as well as in cancers, making them as potential targets for cancer chemotherapy. In the present paper, 3D-QSAR studies were carried out on 4,5-dihydro-1H-pyrazolo[4,3-h]quinazolines against serine/threonine protein kinases viz. polo-like 1 (Plk-1), cyclin dependent 2/A (CDK2/A) and Aurora-A (Aur-A) and their in vitro anti-proliferative activity on A2780 ovarian cancer cell line. Methods: 3D-QSAR models were derived using stepwise forward-backward partial least square (SWFB_PLS) regression method using VlifeMDS QSAR plus software and the docking calculations were carried out using Docking Server. Results: The derived statistically significant and predictive 3D-QSAR models exhibited correlation coefficient r2 in the range of 0.875 to 0.966 and predictive r2 in the range of 0.492 to 0.618. The hydrogen bond donor NH group joining the phenyl ring with quinazoline and terminal amide group were found to favored for Plk-1, CDK2/A and anti-proliferative activity. Estimated energy of binding of compound 45 with enzymes was in the range of -8.52 to -9.03. Conclusion: The results of 3D-QSAR studies may be useful in the development of new pyrazolo[ 4,3-h]quinazoline derivatives with better inhibitory activities against serine/threonine kinases.
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Gou, Xuxu, Beom-Jun Kim, Meenakshi Anurag, Jonathan T. Lei, Meggie N. Young, Matthew V. Holt, Diana Fandino, et al. "Abstract 5011: Targeting kinome reprogramming in ESR1 fusion-driven breast cancer." Cancer Research 83, no. 7_Supplement (April 4, 2023): 5011. http://dx.doi.org/10.1158/1538-7445.am2023-5011.
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Abstract Background: Transcriptionally active ESR1 gene fusions (ESR1-TAF) are a potent cause of estrogen receptor alpha-positive (ERα+) breast cancer endocrine therapy (ET) resistance. These ESR1-TAF are gain-of-function mutations, exhibiting estrogen-independent cell growth, motility and ET resistance. They are not directly druggable because the ERα C-terminal ligand binding domain (LBD) encoding sequence is replaced with a translocated in-frame partner gene sequence. Herein we utilized proteomic approaches to develop novel targeted therapies against ESR1-TAF driven tumorigenesis. Methods: ESR1 fusion cDNA constructs were expressed in ERα+ breast cancer cell lines (T47D and MCF7). Cell growth was assayed by an Alamar blue assay. A mass spectrometry (MS)-based Kinase Inhibitor Pulldown Assay (KIPA) was employed to identify druggable kinases that are commonly upregulated by diverse ESR1-TAFs. A panel of 22 ERα+ patient-derived xenograft (PDX) models were profiled using proteomics and phosphoproteomics to identify models with sensitivity to RET kinase inhibition. Results: KIPA detected an increased abundance of a receptor tyrosine kinase, RET, in T47D cells expressing ESR1-TAFs in an estrogen-independent manner, compared to stable cell lines expressing transcriptionally inactive fusions as well as wild-type ERα protein. Interestingly, RET was also increased when constitutive activating ERα LBD point mutants, Y537S and D538G, were expressed in breast cancer cells. Inhibition of the RET kinase in vitro by repurposing pralsetinib, an FDA-approved RET inhibitor for advanced thyroid and non-small-cell lung cancers, demonstrated a significant reduction in the growth of cells expressing ESR1-TAFs and ERα LBD mutants. These data nominate RET kinase as a common therapeutic vulnerability for ESR1-TAF expressing breast cancers. Proteomic profiling of 22 biologically heterogenous ERα+ PDX tumors defined targetable pathways and predicted tumor subsets that were responsive to RET inhibition therapy. Organoids and xenografts from the pan-ET resistant WHIM18 PDX (that expresses the ESR1-YAP1 TAF) were inhibited by pralsetinib to a similar extent as the CDK4/6 inhibitor palbociclib. These data provide key preclinical rationale for the consideration of RET inhibition for the treatment of ESR1-TAF-driven ET-resistant breast cancer. Interestingly, the growth of WHIM37 PDX (that expresses ERα D538G) that had low level of RET and high level of GFRα-1, the co-receptor of RET, was also suppressed by pralsetinib. This data suggests that either RET or GFRα-1 is a predictive biomarker for RET inhibitor efficacy. Conclusions: Kinome analysis of ESR1 translocated breast tumors using KIPA followed by drug sensitivity studies nominated RET as a new therapeutic target for ET-resistant ERα+ breast cancer. Citation Format: Xuxu Gou, Beom-Jun Kim, Meenakshi Anurag, Jonathan T. Lei, Meggie N. Young, Matthew V. Holt, Diana Fandino, Craig T. Vollert, Purba Singh, Mohammad A. Alzubi, Anna Malovannaya, Lacey E. Dobrolecki, Michael T. Lewis, Shunqiang Li, Matthew J. Ellis, Charles E. Foulds. Targeting kinome reprogramming in ESR1 fusion-driven breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5011.
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Behera, Ranjan, Sarah M. Thomas, and Kojo Mensa-Wilmot. "New Chemical Scaffolds for Human African Trypanosomiasis Lead Discovery from a Screen of Tyrosine Kinase Inhibitor Drugs." Antimicrobial Agents and Chemotherapy 58, no. 4 (January 27, 2014): 2202–10. http://dx.doi.org/10.1128/aac.01691-13.
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ABSTRACTHuman African trypanosomiasis (HAT) is caused by the protozoanTrypanosoma brucei. New drugs are needed to treat HAT because of undesirable side effects and difficulties in the administration of the antiquated drugs that are currently used. In human proliferative diseases, protein tyrosine kinase (PTK) inhibitors (PTKIs) have been developed into drugs (e.g., lapatinib and erlotinib) by optimization of a 4-anilinoquinazoline scaffold. Two sets of facts raise a possibility that drugs targeted against human PTKs could be “hits” for antitrypanosomal lead discoveries. First, trypanosome protein kinases bind some drugs, namely, lapatinib, CI-1033, and AEE788. Second, the pan-PTK inhibitor tyrphostin A47 blocks the endocytosis of transferrin and inhibits trypanosome replication. Following up on these concepts, we performed a focused screen of various PTKI drugs as possible antitrypanosomal hits. Lapatinib, CI-1033, erlotinib, axitinib, sunitinib, PKI-166, and AEE788 inhibited the replication of bloodstreamT. brucei, with a 50% growth inhibitory concentration (GI50) between 1.3 μM and 2.5 μM. Imatinib had no effect (i.e., GI50> 10 μM). To discover leads among the drugs, a mouse model of HAT was used in a proof-of-concept study. Orally administered lapatinib reduced parasitemia, extended the survival of all treated mice, and cured the trypanosomal infection in 25% of the mice. CI-1033 and AEE788 reduced parasitemia and extended the survival of the infected mice. On the strength of these data and noting their oral bioavailabilities, we propose that the 4-anilinoquinazoline and pyrrolopyrimidine scaffolds of lapatinib, CI-1033, and AEE788 are worth optimizing againstT. bruceiin medicinal chemistry campaigns (i.e., scaffold repurposing) to discover new drugs against HAT.
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Hargrave, Darren R., Andrew DJ Pearson, Lucas Moreno, Bruce Morland, Martin Elliott, Guy Makin, Quentin Campbell-Hewson, et al. "A phase I trial of AT9283 (a selective inhibitor of Aurora kinases) given for 72 hours every 21 days via intravenous infusion in children and adolescents with relapsed and refractory solid tumours." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 9542. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.9542.
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9542 Background: AT9283, is a multi-targeted inhibitor, against Aurora A and B, JAK & ABL kinases. Aurora kinases are potential therapeutic targets in paediatric solid cancers. Methods: A phase I dose escalation study was performed using a 72 hour intravenous infusion repeated 3 weekly using a rolling 6 design for patients aged >2 to <19 years with relapsed/ refractory solid tumours. Results: Eighteen patients treated with a median age of 10 (range 3 to 16) years. Four dose cohorts of 7, 9, 11.5 and 14.5 mg/m2/day. The diagnoses included; 5 high grade glioma, 4 rhabdoid tumours, 3 neuroblastomas, 3 sarcomas & 3 others. There has been only one dose limiting toxicity; Grade 3 febrile neutropenia at 11.5 mg/m2/day. The majority of adverse events (AEs) have been grade 1/2 & considered unrelated/ unlikely related to study drug. Two patients have experienced Grade 3 or 4 AEs considered at least possibly related to study drug: Grade 3 haemoglobin and Grade 4 neutrophils in a patient treated at 9 mg/m2/day & Grade 3 lymphopenia, neutrophils, infection with normal neutrophil count and aspartate transaminase in a patient treated at 11.5 mg/m2/day. Pharmacokinetics of AT9283 in this population are largely in keeping with those seen in adult patients at similar doses (Arkenau et al., 2011) although there may be greater variability. Pharmacodynamic evidence of aurora B inhibition, as manifested by a reduction in histone H3 phosphorylation in normal skin biopsies pre & post infusion, has been documented at all dose levels tested. Stable disease (up to 6 cycles) has been observed in 3 patients. Conclusions: This paediatric phase I study has demonstrated AT9283 administered as a 72 hour continuous infusion can be given at a dose level of 11.5 mg/m2/day which is higher than the maximum tolerated dose observed in adult patients (9 mg/m2/day) with advanced solid tumours. Myelosuppresion is the main toxicity but the regimen is well tolerated with preliminary anticancer activity seen in heavily pre-treated paediatric patients. [Table: see text]
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Podesta, Jennifer E., Melanie J. Griffin, Richard Sugar, Matthew S. Squires, Alan Boddy, Spiros Linardopoulos, Andrew DJ Pearson, and Andrew S. Moore. "Adaptation and Validation of the Plasma Inhibitory Activity (PIA) Assay to Detect Inhibition of Aurora, ABL and FLT3 Kinases by AT9283 In Children and Adolescents with Leukaemia." Blood 116, no. 21 (November 19, 2010): 1818. http://dx.doi.org/10.1182/blood.v116.21.1818.1818.
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Abstract Abstract 1818 Non-invasive assessment of biomarker modulation is critically important when conducting early phase trials of targeted therapeutics, particularly in children. Measuring target modulation using primary leukaemic blasts is challenging, since obtaining bone marrow is invasive and invariably requires a general anaesthetic in children. Furthermore, in many cases only a limited number of circulating blasts can be detected in peripheral blood and these may be rapidly cleared upon commencement of effective therapy. For these two reasons, pharmacodynamic (PD) assays using surrogate biological material can be invaluable. The plasma inhibitory activity (PIA) assay was initially developed for FLT3 inhibitors and is currently used in clinical trials to assess ex vivo inhibition of FLT3 kinase and guide optimal dosing (Levis M et al, Blood 2006). Briefly, the assay involves incubating reference leukaemic cell lines in plasma from patients treated with FLT3 inhibitors then assessing the degree of FLT3 inhibition by western blotting. Inhibition of FLT3 in leukemia cell lines has been shown to correlate with inhibition in primary leukaemic blasts. Aurora kinase inhibitors are emerging as promising new agents with activity in leukaemia (Moore AS et al, Leukemia 2010). AT9283 is a novel Aurora kinase inhibitor with activity against the secondary kinase targets FLT3 and ABL (Howard S et al, J Med Chem 2009). We therefore hypothesised that the PIA assay would be applicable as an ex vivo PD assay to simultaneously detect inhibition of these target kinases in leukaemic cell lines: Aurora with FLT3 and Aurora with ABL. Furthermore, we hypothesised that the assay could be adapted to paediatric patients, where limited volumes of blood are available for PD studies. Here we report the validation of the PIA assay for use with AT9283 using leukaemic cell lines incubated in human plasma spiked with clinically relevant concentrations of AT9283 known to inhibit Aurora kinase in primary leukaemic blasts. The PIA assay proved to be a robust means of semi-quantitatively detecting concentration-dependent inhibition of Aurora kinase in the FLT3-ITD positive AML cell line MOLM-13 and the CML cell line K-562. The PIA assay was also effective at qualitatively detecting the inhibition of FLT3 signaling in MOLM-13 cells and ABL signaling in K-562 cells. Of importance to paediatric patients, the assay was successfully performed using 0.5 mL of plasma, half the volume described in the original PIA assay for FLT3 inhibitors. It will be used to assess target kinase modulation in a phase I trial of AT9283 in children and adolescents with relapsed and refractory acute leukaemia (EudraCT No. 2009–016952-36). In conclusion, the PIA assay is applicable not only to FLT3 inhibitors, but also Aurora kinase inhibitors and potentially, other multi-kinase inhibitors. By simultaneously detecting multiple kinase inhibition, the PIA assay may help delineate important mechanisms of action for novel anti-leukaemic drugs. Disclosures: Podesta: The Institute of Cancer Research: Employment, The Institute of Cancer Research (ICR) has a commercial interest in drug development programs (www.icr.ac.uk). Authors employed by ICR are subject to a Rewards to Inventors Scheme which may reward contributors to a program that is subsequently licensed. Squires:Astex Therapeutics Ltd: Employment. Linardopoulos: The Institute of Cancer Research: Employment, The Institute of Cancer Research (ICR) has a commercial interest in drug development programs (www.icr.ac.uk). Authors employed by ICR are subject to a Rewards to Inventors Scheme which may reward contributors to a program that is subsequently licensed. Pearson:The Institute of Cancer Research: Employment, The Institute of Cancer Research (ICR) has a commercial interest in drug development programs (www.icr.ac.uk). Authors employed by ICR are subject to a Rewards to Inventors Scheme which may reward contributors to a program that is subsequently licensed. Moore:The Institute of Cancer Research: Employment, The Institute of Cancer Research (ICR) has a commercial interest in drug development programs (www.icr.ac.uk). Authors employed by ICR are subject to a Rewards to Inventors Scheme which may reward contributors to a program that is subsequently licensed.
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Lee, Kyeong, Hossam Nada, Hyun Jung Byun, Chang Hoon Lee, and Ahmed Elkamhawy. "Hit Identification of a Novel Quinazoline Sulfonamide as a Promising EphB3 Inhibitor: Design, Virtual Combinatorial Library, Synthesis, Biological Evaluation, and Docking Simulation Studies." Pharmaceuticals 14, no. 12 (November 30, 2021): 1247. http://dx.doi.org/10.3390/ph14121247.
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EphB3 is a major key player in a variety of cellular activities, including cell migration, proliferation, and apoptosis. However, the exact role of EphB3 in cancer remains ambiguous. Accordingly, new EphB3 inhibitors can increase the understanding of the exact roles of the receptor and may act as promising therapeutic candidates. Herein, a hybrid approach of structure-based design and virtual combinatorial library generated 34 quinazoline sulfonamides as potential selective EphB3 inhibitors. A molecular docking study over EphB3 predicted the binding affinities of the generated library, and the top seven hit compounds (3a and 4a–f), with GlideScore ≥ −6.20 Kcal/mol, were chosen for further MM-GBSA calculations. Out of the seven top hits, compound 4c showed the highest MM-GBSA binding free energy (−74.13 Kcal/mol). To validate these predicted results, compounds 3a and 4a–f were synthesized and characterized using NMR, HRMS, and HPLC. The biological evaluation revealed compound 4c as a potent EphB3 inhibitory lead (IC50 = 1.04 µM). The screening of 4c over a mini-panel of kinases consisting of EGFR, Aurora A, Aurora B, CDK2/cyclin A, EphB1, EphB2, EphB4, ERBB2/HER2, and KDR/VEGFR2, showed a promising selective profile against EphB3 isoform. A dose-dependent assay of compound 4c and a molecular docking study over the different forms of EphB provided insights into the elicited biological activities and highlighted reasonable explanations of the selectivity.
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Moore, Andrew S., Amir Faisal, Vassilios Bavetsias, David Gonzalez de Castro, Chongbo Sun, Butrus Atrash, Melanie Valenti, et al. "Resistance to Selective FLT3 Inhibitors, Driven by FLT3 Ligand and FLT3 Point Mutations, Can Be Overcome with the Dual FLT3-Aurora Kinase Inhibitor CCT241736,." Blood 118, no. 21 (November 18, 2011): 3492. http://dx.doi.org/10.1182/blood.v118.21.3492.3492.
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Abstract Abstract 3492 Mutations of the FLT3 gene, arising from internal tandem duplications (−ITD) or point mutations of the tyrosine kinase domain (−TKD), cause constitutive activation of the FLT3 receptor tyrosine kinase resulting in stimulation of leukemic proliferation. FLT3-ITD mutations confer a poor prognosis in acute myeloid leukemia (AML), whilst the prognostic impact of FLT3-TKD mutations remains unclear. Small molecule inhibition of FLT3 kinase has been a focus of AML drug development for the past decade, but sustained clinical benefits have been limited by pharmacokinetic failures and resistance. Important mechanisms of resistance to small molecule inhibition of FLT3 include the development of secondary mutations in the FLT3 gene, elevated levels of FLT3 ligand (FL) and over-expression of the anti-apoptotic protein, Survivin. We have previously reported that high FL levels induce resistance to the selective FLT3 inhibitor MLN518 (tandutinib) in vitro. Furthermore, prolonged treatment of human FLT3-ITD positive AML cells (MOLM-13) with MLN518 caused resistance and the selection of cells doubly-mutated with FLT3-ITD and a FLT3-TKD (D835Y) point mutation. These resistant cells, termed MOLM-13-RES, also over-express Survivin. Here we demonstrate that such doubly-mutated AML cells are also relatively resistant to the FLT3 inhibitors Sorafenib and AC220 but not the dual FLT3-Aurora inhibitor CCT241736. CCT241736 is a novel, orally bioavailable, imidazo[4,5-b]pyridine derivative discovered at our Institute, highly selective for FLT3 and Aurora kinases with an S(10) selectivity score using KINOMEscan™ technology of 0.057 (fraction of 386 non-mutant kinases inhibited >90% when screened at 1 uM of CCT241736; San Diego, CA). In biochemical kinase studies, CCT241736 has IC50 values against FLT3, Aurora A and Aurora B of 0.035, 0.015 and 0.1 uM respectively. Furthermore, CCT241736 inhibits a wide range of FLT3 mutants, including FLT3-ITD, -D835Y, -D835H, -K663Q and –N841I. In cellular assays, CCT241736 inhibits viability of the human FLT3-ITD positive AML cell lines MOLM-13 and MV-4-11 with EC50 values of 0.1 and 0.27 uM respectively. Unlike the selective FLT3 inhibitors MLN518 and AC220, the in vitro cellular efficacy of CCT241736 is not affected by high levels of FL. In vivo, mouse tumor xenograft models of MOLM-13, MV-4-11, and the doubly-mutated cell line MOLM-13-RES are also sensitive to CCT241736 at well tolerated oral doses, with biomarker modulation consistent with dual inhibition of FLT3 and Aurora kinases. Based on allometric scaling from mouse and rat data, CCT241736 has favorable predicted human pharmacokinetics and phase I clinical trials are planned. In summary, dual inhibition of FLT3 and the critical mitotic kinase Aurora by CCT241736 may represent a novel treatment strategy for FLT3-mutated AML by overcoming the effects of high FL levels and limiting resistance caused by secondary mutations of the FLT3 gene. Disclosures: Moore: The Institute of Cancer Research: Employment. Faisal:The Institute of Cancer Research: Employment. Bavetsias:The Institute of Cancer Research: Employment. Gonzalez de Castro:The Institute of Cancer Research: Employment. Sun:The Institute of Cancer Research: Employment. Atrash:The Institute of Cancer Research: Employment. Valenti:The Institute of Cancer Research: Employment. de Haven Brandon:The Institute of Cancer Research: Employment. Avery:The Institute of Cancer Research: Employment. Pearson:The Institute of Cancer Research: Employment. Workman:The Institute of Cancer Research: Employment. Blagg:The Institute of Cancer Research: Employment. Raynaud:The Institute of Cancer Research: Employment. Eccles:The Institute of Cancer Research: Employment. Linardopoulos:The Institute of Cancer Research: Employment.
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Panicker, Resmi C., Anthony G. Coyne, and Rajavel Srinivasan. "Allosteric Targeting of Aurora A Kinase Using Small Molecules: A Step Forward Towards Next Generation Medicines?" Current Medicinal Chemistry 26, no. 13 (July 8, 2019): 2234–42. http://dx.doi.org/10.2174/0929867324666170727120315.
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Background: Aurora A (AurA) kinase is a key mitotic protein implicated in cancer. Several small molecule inhibitors targeting the ATP binding site of this enzyme are in various stages of clinical development. However, these inhibitors can result in selectivity and drug resistance problems. Allosteric inhibition of kinases using small molecules is an alternative strategy to target these enzymes selectively and these could serve as the seeds for next generation medicines. This review discusses the developments in the non-ATP site binding small molecule inhibitors of AurA and their prospect as future therapeutics. Discussion: Allosteric targeting of AurA kinase using small molecules is relatively a new strategy, and only a handful of research work has been reported. Two patents and three papers pertaining to allosteric targeting of AurA kinase using small molecules were covered in this review. Topics discussed include, identification of small molecule inhibitors targeting AurA- Targeting Protein for Xenopus kinesin-like protein 2 (TPX2) interaction, anacardic acid - a natural product ligand that selectively modulates AurA activity in the presence of Aurora B kinase, and identification of felodipine as an uncompetitive inhibitor of AurA using Surface Enhanced Raman Spectroscopy (SERS) technique Conclusion: Allosteric targeting of therapeutically relevant enzymes using small molecules is a burgeoning research area. New techniques such as fragment-based ligand discovery, SERS methods, etc., are expanding to identify the allosteric site binding ligands. Research in this area is expected to deliver fruitful outcome in terms of novel therapeutics against AurA kinase as well as other therapeutically relevant enzymes.
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Hembrough, Todd A., Xiaoru Chen, Patricia A. Burke, Glenn M. Swartz, Kathleen Bengali, Richard Brokx, Theresa M. LaVallee, and Mark R. Bray. "Inhibition of Multiple Myeloma Tumor Growth and FGFR3 by the Aurora-Angiogenesis Inhibitor ENMD-981693." Blood 110, no. 11 (November 16, 2007): 1209. http://dx.doi.org/10.1182/blood.v110.11.1209.1209.
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Abstract ENMD-981693 is a novel, orally-active antimitotic and antiangiogenic molecule that was discovered through a screening effort directed towards Aurora kinases. In addition to activity against Aurora A (AurA), ENMD-981693 is a potent inhibitor of several tyrosine kinases which drive the neo-vascularization of growing tumors, namely JAK2, VEGFR2 (KDR), PDGFRα and the FGF receptor family members FGFR1, R2, and R3. Multiple myeloma (MM) is a disease in which AurA and angiogenesis have been shown to play a role in disease progression. In addition, up to 15% of MM patients have a t(4;14) translocation, which leads to ectopic overexpression of the FGFR3, and is associated with a poor clinical outcome. In preclinical models, inhibitors of FGFR3 have exhibited antitumor activity towards t(4;14) bearing MM tumors. In in vitro proliferation assays, ENMD-981693 demonstrated an IC50 of ∼2 μM towards several MM cell lines, including H929, U266 and RPMI-8226. In immunoprecipitation studies, ENMD-981693 inhibits the kinase activity of both FGFR3 (IC50 ∼0.8 μM) and JAK2 (IC50 ∼0.5 μM) in the MM cell lines U266 and H929. These activities are in accord with the inhibitory activity of ENMD-981693 on the purified kinase domains of FGFR3 (IC50=0.5 μM) and JAK2 (IC50=0.12 μM). ENMD-981693 also inhibits activation of JAK2 activity in the HEL cell line which expresses the polycythemia vera mutated form of JAK2 (V617F). Mice implanted with H929 tumor xenografts were treated for 4 days with 75 – 225 mg/kg/d of the tartrate salt of ENMD-981693 (ENMD-2076). The amount of phosphorylated (and thus activated) FGFR3 immunoprecipitated from lysates of H929 tumors showed a significant decrease following drug treatment with no change in total FGFR3. In complementary immunoprecipitation studies, a similar decrease in JAK2 activity was seen in these H929 tumors treated with ENMD-981693 tartrate. Daily, oral treatment of RPMI-8226 xenografts with ENMD-981693 tartrate (225 mg/kg) resulted in a significant (67%) reduction in tumor burden. Follow up studies will assess the activity of ENMD-981693 tartrate on MM tumor xenografts which harbor the t(4;14) translocation, and whose growth is largely driven by FGFR3. Taken together, ENMD-981693 has been identified as a single agent that targets multiple critical mediators of MM growth, and angiogenesis. This suggests that ENMD-981693 has the potential for clinical activity in MM, particularly in patients with the t(4;14) translocation and in polycythemia vera patients with mutated JAK2. An IND filing is planned for ENMD-981693 in 2007.
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Lotfi, Shamim, Aarthi Jayanthan, Victor A. Lewis, Greg Guilcher, Matthew S. Squires, Todd Cooper, and Aru Narendran. "AT9283, A Novel Aurora Kinase/Jak2 Inhibitor Demonstrates Activity against Refractory Infant Leukemia Cells: Studies On Growth Inhibition, Biological Correlates, Drug Synergy and Effects On Leukemia Stem-Like Cells." Blood 114, no. 22 (November 20, 2009): 3078. http://dx.doi.org/10.1182/blood.v114.22.3078.3078.
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Abstract Abstract 3078 Poster Board III-15 Leukemia in children less than 1 year of age confers a poor prognosis, despite intensification of therapy. These leukemias possess unique biologic characteristics including the presence of mixed-lineage leukemia (MLL) gene rearrangement and high expression of Fms-like tyrosine kinase 3 (FLT3). AT9283, a potent inhibitor of Aurora A and B kinases, JAK2, JAK3, and mutant Abl Kinase, has demonstrated inhibition of multiple solid tumor cell lines in vitro and in mouse xenograft models. Aurora kinase inhibition has been shown to inhibit cancer cell growth by interfering with the mitotic apparatus. We investigated the activity of AT9283 against cell lines derived from refractory infant leukemia cells to identify its efficacy in a future treatment protocol. Method Five cell lines derived from infant leukemia cells were used (ALL: BEL1, KOPN8, KCCF2, B1 and AML: TIB202). We also included the cell line SEM that was derived from a 5 year old child with t (4;11) MLL-AF4 preB-ALL. Normal bone marrow stromal cells were used to evaluate cytotoxicity against non-malignant cells. AT9283 was provided by Astex Therapeutics Ltd. (Cambridge, UK). Approximately 1×104 cells per well were seeded in 96-well plates and incubated with increasing concentrations of AT9283, alone or in combination with a panel of conventional and novel therapeutic agents. After four days, cell survival was measured by Alamar blue assay and IC50 values and combination indices were calculated. Stem-like cells were quantified by the distribution of ALDH bright cells by Aldefluor assay (Stem cell technologies) and characterized by conventional clonogenic assays. Alterations in cell-signaling pathways and survival proteins were measured by Western blot analysis using total and phospho-specific antibodies. Results AT9283 inhibited the growth of all five cell lines with a 10 fold variation in IC50 within cell lines (IC50 range, 0.1 to 0.01 μM). There was a corresponding increase in the number of cells displaying a polyploid phenotype, an effect of aurora kinase inhibition. No significant cytotoxicity against bone marrow stromal cells was seen under the experimental conditions used in this study (IC50 > 10 μM). Changes in the activation and expression of a variety of intracellular proteins were noted, including the down regulation of activated ERK1/2, MYC and AKT within 10 minutes of exposure to the agent. An increase in the activated form of RAF and ATF2 was observed immediately after drug exposure. Importantly, a significant decrease in the level of constitutive pFLT-3 was demonstrated. A concurrent increase in cleaved PARP was also noted, indicating the initiation of apoptosis. In combination studies, the HDAC inhibitor Apicidin showed synergy across all cell lines (CI range: 0.07 to 0.62). A decrease in ALDH bright stem-like cells was observed in a dose dependent manner, up to 50% over 24 hours at IC50 concentrations. Conclusions Our in vitro studies show that AT9283 significantly decreases the growth and survival of infant leukemia cell lines. Importantly, AT9283 potently induces FLT3 de-phosphorylation, inhibiting a critical growth stimulatory pathway of infant ALL cells. We have identified changes in a number of signaling and apoptotic molecules that can provide a panel of markers for biological correlative analysis for drug activity in vivo. Also, the drug combination studies demonstrate the potential of HDAC inhibition to synergize with the activity of this agent. Finally, the effect on stem-like cells provides a rationale and critical preclinical data for the formulation of an effective clinical trial for the treatment of infants with refractory ALL. Disclosures Squires: AstexTherapeutics Ltd: Employment.
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Santo, Loredana, Teru Hideshima, Diana Cirstea, Madhavi L. Bandi, Erik A. Nelson, Hiroshi Ikeda, Sonia Vallet, et al. "AT9283, a Small Molecule Multi-Targeted Kinase Inhibitor with Potent Activity Against Aurora Kinase and STAT3 In Combination with Lenalidomide Results In Synergistic Anti-Myeloma Activity." Blood 116, no. 21 (November 19, 2010): 2994. http://dx.doi.org/10.1182/blood.v116.21.2994.2994.
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Abstract Abstract 2994 Despite recent advances with new drugs such as bortezomib, thalidomide and lenalidomide, multiple myeloma (MM) remains an incurable disease. Used as single agents, these compounds have shown marked antitumor activity, but the number of patients with relapsed and refractory disease remains high. Combination of these agents with other classes of novel drugs would offer great promise to improve patient outcome. AT9283 (Astex therapeutics, Cambridge UK) is a multi-targeted kinase inhibitor that inhibits Aurora A (AURKA), Aurora B (AURKB) and Janus Kinase (JAKs). AURKA and AURKB expression has been correlated with genetic instability and cellular proliferation in MM; therefore, Aurora kinases represent an attractive therapeutic target in MM. In addition the JAK/STAT pathway plays an important role in the survival and proliferation of MM cells. Blocking this pathway may therefore be critical for the survival of MM cells. AT9283 decreased both phospho-Histone H3 and the phosphorylation of Aurora A at Thr 288 in Nocodazole treated cells, suggesting the dual activity of AT9283 against AURKA and AURKB. Importantly, besides Aurora kinase inhibition, we observed that AT9283 inhibited STAT3 tyrosine phosphorylation within 30 minutes of treatment. The effect of AT9283 on pSTAT3 inhibition was further investigated by using U3A cells stably expressing a luciferase reporter gene under the control of a STAT-dependent promoter. AT9283 inhibited STAT3-dependent luciferase activity with an EC50 of approximately 0.125 μ M. Consistent with AT9283 induced cytotoxicity, genetic depletion of STAT3, AURKA or AURKB showed growth inhibition of MM cells, suggesting that AT9283-induced inhibition of these molecules is in part the underlying mechanism of MM cell growth inhibition. In vivo data using a xenograft mouse model of human MM show that mice treated with AT9283 demonstrated slower tumor growth compared to the control group (p=0.018) and prolongation in median overall survival (32 days in treated group versus 18 days in control group; p < 0.0001) without adverse effects. We next evaluated the activity of AT9283 in combination with established MM drugs and strong synergistic effect was found when AT9283 was combined with lenalidomide (Selleck Chemicals LLC, TX, USA) (Combination Index < 0.9). We hypothesized that the synergistic effect of this combination is due to the fact that the two drugs target different pathways and different phases of the cell cycle, thus augmenting their individual anti-myeloma activity. We examined MM cell cytotoxicity of the combination by using AT9283 and lenalidomide at concentrations lower than their maximal cytotoxic concentrations. Increasing doses of AT9283 (0 -0.125 μ M) were added to lenalidomide (0-2μ M) and a significant decrease in viability (as measured by MTT and cell growth as determined by 3H-TdR at 48 h) was observed with combined therapy compared to either agent alone. A significant increase (55.7%) in early and late apoptosis occurred after 72 hours of exposure of cells to combined therapy with associated caspase-8 and PARP cleavage. Combination treatment resulted in downregulation of pSTAT3 and pERK following 4 hours of treatment. Considering the role that the BM microenvironment plays in growth and survival of MM cells, we examined whether the combination of low dose AT9283 plus lenalidomide induced MM cell death in the context of the BM microenvironment. MM.1S cells were cultured with or without BMSCs in the presence or absence of AT9283, lenalidomide or in combination regimen. Combined therapy inhibited 3H-TdR uptake of MM.1S cells cultured in the presence of BMSCs. Interestingly, we observed that AT9283 plus lenalidomide downregulated the expression of the p-STAT3 and p-ERK when MM.1S cells were cultured with BMSCs, highlighting the role of this drug combination in overcoming the protective effect of BMSCs. These results provide the rationale for the clinical evaluation of AT9283 in combination with lenalidomide in MM patients. Disclosures: Squires: 3Astex Therapeutics Ltd: Employment. Anderson:MILLENNIUM: Consultancy; CELGENE: Consultancy; NOVARTIS: Consultancy; MERCK: Consultancy; ONYX: Consultancy; BMS: Consultancy. Raje:novartis: Consultancy; celgene: Consultancy; astra zeneca: Research Funding; acetylon: Research Funding.
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Chang, Bill H., Jessica Leonard, Joelle Wolf, Michelle Degnin, Kyle Lenz, Beth Wilmot, Charles G. Mullighan, et al. "Significant In Vivo Sensitivity to Aurora Kinase Inhibition in TCF3-Hlf rearranged Acute Lymphoblastic Leukemia." Blood 132, Supplement 1 (November 29, 2018): 4026. http://dx.doi.org/10.1182/blood-2018-99-115706.
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Abstract Acute Lymphoblastic Leukemia (ALL) harboring the t(17;19)(q22;p13) is a rare subtype of leukemia with a dismal prognosis. This recurring translocation produces an aberrant TCF3-HLF fusion with distinct gene expression profiles and drug sensitivity. Recent studies have shown that this subtype of ALL might be targeted using therapies inhibiting BCL-2 and the pre-B cell receptor through inhibition of SRC family kinases. However, preliminary validation of these studies have revealed significant heterogeneity of response to BCL-2 and SRC inhibitors. As such, we sought to identify other possible targets that could overcome this heterogeneity and improve response to therapy. Methods: One local as well as four other samples from the Children's Oncology Group's ALL Biorepository with TCF3-HLF ALL were expanded in immunodeficient NSG mice. All samples were verified by RT-PCR and Sanger sequencing for the fusion transcript. Samples were then interrogated with our functional drug screen that is comprised of compounds with activity against two-thirds of the tyrosine kinome as well as other non-tyrosine kinase pathways, including RAF/MEK/MAPKs, PI3K/AKT/mTOR, AMPK, ATM, Aurora kinases, CAMKs, CDKs, GSK3a/b, IKK, PKA, PKC, PLK1, and RAF as well as BCL2 family, BRD4, IDH1/2, Hedgehog, HSP90, NOTCH/g-secretase, proteasome, survivin, STAT3, and WNT/b-catenin. The samples were sequenced using the Agilent SureSelect Strand-Specific RNA Library Preparation Kit on the Bravo robot (Agilent). All five patient samples successfully engrafted into NSG mice and were tested for in vivo sensitivity as assessed for disease burden or survival. Results: Three patient samples were identified to carry Type I translocations fusing exon 13 of TCF3 with variable intronic insertions followed by exon 4 of HLF. All three type I translocations produced different fusions due to different lengths within the variable region. One sample predicted a truncation product of TCF3 ending in exon 13 with an early stop codon within the variable region. Two patient samples carried the identical type II translocation fusing Exon 12 of TCF3 with exon 4 of HLF. RNA-seq results of the five samples identified other individual translocations, but none involved other specific disease related lesions. Results from our drug screen showed significant heterogeneity in response to the majority of drugs assayed including the ABL/SRC inhibitor dasatinib and the BCL-2 inhibitor venetoclax. Further, in vivo studies exposing cohorts of animals to vehicle (n=5), dasatinib (40mg/kg/day; n=5), venetoclax (25-100mg/kg/day; n=5) or combination of dasatinib and venetoclax (n=5) identified only two samples with treatment benefit. Interestingly, review of the results of the drug screen suggested hypersensitivity to aurora kinase inhibitors. Each sample was tested in vivo in cohorts of vehicle (n=5) and alisertib (30mg/kg/day; n=5). All five ALL samples showed significant response (p<0.01 for all five samples compared to their respective vehicle controls by Chi Square analysis). All animals tolerated treatment and no animal showed significant hematologic toxicity from treatment with drugs. Conclusion: Our results suggest that TCF3-HLF ALL is a heterogeneous subset of ALL with both different gene expression patterns from TCF3-HLF to other fusions as well as functional drug response. In vivo validation in the murine model with these five samples suggests significant heterogeneity to current pursued targets such as BCL-2 and SRC compared to previously published reports. Most intriguing, all samples tested with alisertib identified significant in vivo response suggesting unique preclinical support to pursue further clinical testing within this rare and lethal subtype of ALL. Disclosures Leonard: Amgen: Research Funding. Mullighan:Loxo Oncology: Research Funding; Pfizer: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Abbvie: Research Funding; Cancer Prevention and Research Institute of Texas: Consultancy. Tyner:Takeda: Research Funding; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; Array: Research Funding; Genentech: Research Funding; Incyte: Research Funding; Constellation: Research Funding; Aptose: Research Funding; Janssen: Research Funding; AstraZeneca: Research Funding; Gilead: Research Funding. Druker:GRAIL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Research Funding; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees, Research Funding; Patient True Talk: Consultancy; Fred Hutchinson Cancer Research Center: Research Funding; ARIAD: Research Funding; Beta Cat: Membership on an entity's Board of Directors or advisory committees; Oregon Health & Science University: Patents & Royalties; McGraw Hill: Patents & Royalties; Novartis Pharmaceuticals: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; MolecularMD: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Henry Stewart Talks: Patents & Royalties; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Monojul: Consultancy; Celgene: Consultancy; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; Aileron Therapeutics: Consultancy; Aptose Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millipore: Patents & Royalties.
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Griffin, Patrick, Steffan T. Nawrocki, Takashi Satou, Claudia M. Espitia, Kevin R. Kelly, Maki Hasegawa, Swaminathan Padmanabhan, Angela Romanelli, Ron de Jong, and Jennifer S. Carew. "The Investigational Multi-Targeted Kinase Inhibitor TAK-901 Antagonizes Acute Myeloid Leukemia Pathogenesis: Results of Preclinical Studies." Blood 118, no. 21 (November 18, 2011): 581. http://dx.doi.org/10.1182/blood.v118.21.581.581.
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Abstract Abstract 581 The long-term prognosis for the majority of patients diagnosed with acute myeloid leukemia (AML) is very poor due, in part, to pre-existing myelodysplasia, multidrug resistance, and co-existing morbidities that limit therapeutic options. Novel strategies are essential in order to improve clinical outcomes. TAK-901 is an investigational small molecule kinase inhibitor that is currently being evaluated in Phase I trials. In preclinical studies, TAK-901 has demonstrated significant effects against a number of kinases with important roles in cancer including the Aurora kinases, which are key regulators of mitosis and whose overexpression in cancer promotes genetic instability, malignant pathogenesis, and drug resistance. We hypothesized that simultaneously targeting the activity of the Auroras and other oncogenic kinases with TAK-901 would disrupt AML pathogenesis. In order to test our hypothesis, we investigated the efficacy and pharmacodynamic activity of TAK-901 human AML cell lines, primary AML specimens, and an orthotopic bioluminescent disseminated mouse model of AML. TAK-901 potently diminished the viability of a panel of 8 AML cell lines as well as primary cells obtained from patients with AML. Acute exposure to TAK-901 ablated clonogenic survival, triggered the accumulation of polyploid cells, and induced apoptosis. The cytostatic and cytotoxic effects of TAK-901 were associated with significantly increased expression of the cyclin-dependent kinase inhibitor p27, growth arrest and DNA-damage-inducible 45a (GADD45a), and the BH3-only pro-apoptotic protein PUMA. Chromatin immunoprecipitation (ChIP) assays revealed that the elevation in the expression of these genes caused by administration of TAK-901 was due to increased FOXO3a transcriptional activity. The in vivo anti-leukemic activity of TAK-901 was investigated in a disseminated xenograft mouse model of AML established by intravenous injection of luciferase-expressing MV4-11 cells. IVIS Xenogen imaging was utilized to monitor disease burden throughout the study. In this mouse model, administration of TAK-901 was very well-tolerated and significantly more effective than the standard of care drug cytarabine with respect to suppressing disease progression and prolonging overall survival. Analysis of specimens collected from mice demonstrated that TAK-901 inhibited the homing of AML cells to the bone marrow microenvironment and induced AML cell apoptosis in vivo. Our collective findings indicate that TAK-901 is a novel multi-targeted kinase inhibitor that has significant preclinical activity in AML models and warrants further investigation. Disclosures: Satou: Takeda Pharmaceuticals: Employment. Hasegawa:Takeda Pharmaceuticals: Employment. Romanelli:Millennium Pharmaceuticals: Employment. de Jong:Takeda San Diego: Employment. Carew:Millennium Pharmaceuticals: Research Funding.
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Li, Lingxiao, Praechompoo Pongtornpipat, Soham D. Puvvada, and Jonathan H. Schatz. "Targeting MYC Expression With CDK Inhibitors Shows Potency In Preclinical Models Of High-Risk Diffuse Large B-Cell Lymphom." Blood 122, no. 21 (November 15, 2013): 1831. http://dx.doi.org/10.1182/blood.v122.21.1831.1831.
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Abstract Diffuse large B-cell lymphoma is the most common lymphoid malignancy and results in death in a third or more of patients. R-CHOP chemoimmunotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) is the front-line standard of care, but better treatments are needed for patients who are at high risk of failing this regimen. Recent studies found that co-expression of the oncogenic transcription factor MYC and the antiapoptotic protein BCL2, detected by immunohistochemistry, is a reliable predictor of risk: Less than 40 percent of R-CHOP-treated patients with co-expressing tumors will achieve long-term disease-free survival. Inhibition of cell-cycle promoting kinases is a rational approach in high-risk DLBCL because of frequent deregulation detected by high-resolution cytogenetics and other methods. We studied a panel of inhibitors against multiple members of the cyclin-dependent kinase (CDK) family, the aurora kinases, and other cell-cycle kinase targets in models of MYC-BCL2 co-expressing DLBCL. The multi-CDK inhibitor dinaciclib emerged with particularly high potency, with IC50 5 nM or less against multiple human cell lines. The drug also had strong activity against a genetically defined murine lymphoma model driven by MYC and BCL2, which accurately reflects the pathology and clinical behavior of high-risk DLBCL. Dinaciclib alone is sufficient to kill MYC-BCL2 DLBCL, as neither chemotherapy drugs nor other kinase inhibitors showed synergy. Mechanistically, the drug targets CDK1, 2, 5, and 9, and any or all of these could contribute to its potency against these tumors. CDK1 and 2 directly promote progression through the cell cycle by phosphorylating the retinoblastoma (Rb) protein. But we found loss of Rb phosphorylation not to be a reliable marker of potency. Previous studies of other multi-CDK inhibitors, meanwhile, have pointed to lost expression of the antiapoptotic factor MCL1, an effect of CDK9 inhibition, to be a key anti-tumor activity. We find high potency of dinaciclib, however, in multiple systems with constitutive expression of BCL2, which can replace MCL1 in protecting cells from apoptosis. Instead, most reliably, we found loss of c-MYC gene transcription to be a key effect of dinaciclib therapy, resulting in rapid loss of MYC protein and tracking with the drug’s potency. CDK1 regulation of SMAD3 and CDK9 regulation of RNA polymerase II are mechanistic possibilities we are exploring to explain the effect on c-MYC transcription. Either way our study shows the promise of CDK inhibition to improve prognosis for high-risk DLBCL and points to c-MYC regulation as a key mechanism. Dinaciclib is entering phase 3 clinical evaluation in other tumor types and may be appropriate for evaluation in DLBCL based on our work, although it remains to be determined if this drug’s pharmacologic properties would permit replication of the mechanism we see preclinically. By precisely defining the mechanism by which CDK inhibition targets MYC expression, however, our study promotes development of more precise therapies for high-risk DLBCL in the future. Disclosures: No relevant conflicts of interest to declare.
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Brummendorf, Tim H., Artur Gontarewicz, Gunhild Keller, Jürgen Moll, Melanie Braig, Imke Rohe, Edgar Jost, et al. "Resistance to Danusertib (formerly PHA-739358) in BCR-ABL-Positive Cells Is Mediated by Upregulation of the Drug Transporter Abcg2 and Can Be Suppressed in Vitro by Combination Treatment with Imatinib." Blood 114, no. 22 (November 20, 2009): 1724. http://dx.doi.org/10.1182/blood.v114.22.1724.1724.
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Abstract Abstract 1724 Poster Board I-750 The success of imatinib (IM, formerly STI571, Gleevec®) in the treatment of chronic myeloid leukemia (CML) is compromised by the development of primary or acquired IM-resistance, particularly in advanced phase disease as well as by a limited IM-effect on immature hematopoietic stem cells, emphasizing the need for novel therapeutic strategies. The small molecule inhibitor Danusertib (formerly PHA-739358) potently inhibits Aurora and ABL kinases. Here, the individual contribution of each pathway to the effect of Danusertib was investigated. Starting at very low concentration, a dose-dependent reduction of BCR-ABL activity was observed, whereas inhibition of Aurora kinase activity, assessed by phosphorylation of histone H3-Ser10, required substantially higher concentrations. In primary CD34+ CML cells, including initially quiescent leukemic stem cells, combination therapy with IM and Danusertib revealed a synergistic anti-proliferative activity, which also affected immature CD34+38- cells. Neither mono- nor combination therapy led to substantial induction of apoptosis in quiescent stem cells. Interestingly, under treatment with Danusertib, the emergence of resistant clones in a well-established murine Ba/F3-p210 cell model was considerably less frequent than with IM. Surprisingly, Danusertib-resistant cells did not have mutations in BCR-ABL or Aurora kinase domains and remained IM-sensitive. Analysis of resistance mechanisms using DNA-microarray suggests an overexpression of Abcg2 efflux transporter to be causative for the resistance arising under Danusertib treatment. In support of this finding, stable retroviral overexpression of Abcg2 in parental Ba/F3-p210 cells induced a resistant phenotype against Danusertib. Furthermore, the Abcg2 inhibitor Fumitremorgin C (FTC) could restore the sensitivity of resistant cells to Danusertib. Finally, significant re-expression of Abcg2 in parental Ba/F3-p210 cells upon treatment with the demethylating agent 5-Azacytidine suggests that an epigenetic mechanism might play a role in the regulation of Abcg2 gene expression in resistant clones. Detailed analyses of the methylation patterns of the Abcg2 promoter region are currently being performed. In conclusion, simultaneous in vitro exposure of Ba/F3-p210 cells to Danusertib and IM significantly reduced the emergence of drug resistance, raising hope that both epigenetic modulation of drug transporters involved in development of resistance as well as hypothesis-driven combinations of kinase inhibitors may eventually achieve durable disease control even in 2nd and 3rd line treatment of CML. Disclosures Brummendorf: Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Moll:Nerviano MS: Employment. Jost:MSD: Research Funding. Bokemeyer:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Holyoake:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squib: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Balabanov:Novartis : Research Funding; Bristol Myers Squibb: Research Funding.
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Giles, Francis, Jorge Cortes, Donald A. Bergstrom, Alan Xiao, Penny Bristow, Dan Jones, Srdan Verstovsek, Deborah Thomas, Hagop Kantarjian, and Steven J. Freedman. "MK-0457, a Novel Aurora Kinase and BCR-ABL Inhibitor, Is Active Against BCR-ABL T315I Mutant Chronic Myelogenous Leukemia (CML)." Blood 108, no. 11 (November 16, 2006): 163. http://dx.doi.org/10.1182/blood.v108.11.163.163.
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Abstract Background. MK-0457 (VX-680) is a small-molecule inhibitor of aurora kinases A, B, and C, and wildtype and mutant BCR-ABL, including the T315I variant. The T315I BCR-ABL mutation mediates high level resistance to imatinib, dasatinib and nilotinib. MK-0457 has in vitro activity against cells expressing wild-type or mutated BCR-ABL, including the T315I BCR-ABL mutation, at a concentration of ~1μM. A Phase I study of MK-0457 is being conducted in patients with refractory hematologic malignancies, including CML. Methods. After IRB approval, 15 consenting patients with refractory CML (median 5 prior regimens), ECOG performance status ≤2, and adequate organ function were enrolled using a standard dose escalation scheme with 3 patients/dose level until dose-limiting toxicity (DLT), followed by 6 patients/level. MK-0457 was administered by continuous 5-day intravenous infusion every 2 to 3 weeks. DLT was defined as grade 3 or higher non-hematologic toxicity during cycle 1. Pharmacokinetics (PKs) were collected pre-dose through 168 h and analyzed for MK-0457 by HPLC/mass spec. Steady state volume of distribution (Vdss), clearance (CL), maximal concentration (Cmax) and terminal half-life (t1/2) were determined by WinNonLin. Results. Fifteen CML patients received MK-0457 dosed at 8, 12, 16, 20, 24, 28, and 32 mg/m2/hr. All but three of these patients had a history of accelerated phase or blast crisis. Eleven of these patients carried the BCR-ABL T315I mutation. All eleven BCR-ABL T315I mutant CML patients demonstrated clinical signals of anti-leukemic activity. By conventional criteria, there was one major hematological response, four minor hematological responses, one complete cytogenetic response, two partial cytogenetic responses, and one minimal cytogenetic response. Some degree of molecular response, as measured by BCR-ABL:ABL transcript ratio, was detected in five of six patients for whom such data were available. The longest a patient was treated was for 15 cycles, and is still ongoing. The patients with the best clinical response had the largest magnitude inhibition of BCR-ABL in leukemia cells as measured by levels of phosphoCRKL, a substrate of the BCR-ABL fusion kinase. None of the patients without the BCR-ABL T315I mutation showed objective responses. Remarkably, no drug-related non-hematological toxicity was observed. Some patients had apparent myelosuppression, which is an expected mechanism-based side effect of Aurora kinase inhibition. Plasma concentrations reached steady state rapidly (i.e., within 24 h) and declined biexponentially after the end of infusion; after a rapid initial decay, a slower decaying terminal phase demonstrated a t1/2 ~15 h. Steady state plasma concentrations are ≥ 1μM at a dose level of ≥ 20 mg/m2/hr. Conclusion. MK-0457 is very well tolerated and achieves plasma levels similar to those causing efficacy in preclinical models of CML. MK-0457 is the first T315I BCR-ABL inhibitor to show activity against this highly refractory, poor prognostic subpopulation of CML. Further evaluation of MK-0457 alone and in combination with other BCR-ABL inhibitors in CML is warranted.
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Gauler, Thomas Christoph, Benjamin Besse, Silvia Novello, Egbert F. Smit, Elizabeth R. Plummer, Jean-Pierre Delord, Maurizio Nicodemo, et al. "Phase II study of danusertib (D) in advanced/metastatic non-small cell lung cancers (NSCLC)." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e19138-e19138. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e19138.
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e19138 Background: D is an ATP competitive pan-aurora kinases inhibitor with activity also against FGFRs, VEGFR, Ret, TrkA, Scr, and Abl. Methods: Eligible pts had NSCLC progressing for advanced/metastatic disease after 1 prior chemotherapy line (CT). Primary endpoint was progression-free survival at 4 months (PFS-4) evaluated in a Simon two-stage design. Number of successes required for not rejecting the alternative hypothesis (40% PFS-4) was ≥4/19 evaluable pts while the number of successes required to reject at the end of stage 2 the null hypothesis (20% PFS-4) was ≥11/36 (α 1-sided = 0.1). D was administered at 500 mg/m² as 24 hr IV infusion q2w. The expression of Aurora A/B, TPX-2, MDR, Scr, Survivin by IHC and the amplification of FGFR1 by FISH on tumor biopsies of consenting pts were evaluated. Results: 3 out of 19 evaluable pts were PFS-4 at the end of the 1st stage, thus precluding passage to the 2nd stage. Interestingly, in pts with squamous (SCC) (n=7), median PFS and OS were 6.4 and 10.6 mos respectively (vs. 2.2 and 7.6 mos, in non-SCC pts), suggesting a possible specific effect in this subtype. Additional pts with SCC were therefore treated under a protocol amendment. At the end of this 2nd stage, 5/31 evaluable SCC pts (80% CI: 0.08-0.28) were PFS-4 indicating that the predefined threshold required to conclude for activity would not have been reached. Overall 56 pts, all histology NSCLC, were treated: median age 62 yrs (39-79), 64% male, 70% SCC, 36% with >1 prior CT. Best response was a PR in 1 pt and SD in 20 pts; median PFS and OS were 2.1 and 8.3 mos respectively. The most frequent drug-related AEs (any Grade, ≥20%) were: uncomplicated and short lasting neutropenia (94%), nausea (39%), fatigue (37%), asthenia (30%), anorexia and diarrhea (29%), alopecia (23%). Histological analyses by IHC and FISH is still ongoing: results will be presented. Conclusions: Limited evidence of activity was observed, insufficient to meet the predefined threshold to call efficacy in NSCLC when D was administered as monotherapy at this dose/schedule. D confirmed to have a manageable safety profile. Clinical trial information: 2006-003772-35.
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Shah, Pooja A., Tuhina Mazumdar, Reid T. Powell, Li Shen, Jing Wang, Clifford C. Stephen, Mitchell J. Frederick, and Faye M. Johnson. "Abstract 2847: Concurrent inactivation of PI3K and PLK1 is synergistic and overcomes acquired resistance to PI3K inhibitors in NOTCH1MUT HNSCC." Cancer Research 83, no. 7_Supplement (April 4, 2023): 2847. http://dx.doi.org/10.1158/1538-7445.am2023-2847.
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Abstract Targeted therapies are limited for head and neck squamous cell carcinoma (HNSCC), as it is driven by mutations in tumor suppressors, including NOTCH1. We previously identified loss of function NOTCH1 mutations in HNSCC to be sensitive to phosphoinositide-3 kinase (PI3K) inhibitors through sustained Aurora kinase B levels. However, therapy resistance and modest responses are the leading causes of failure for targeted therapies. To address this pressing clinical need, we sought to identify drugs that would enhance the efficacy of PI3K inhibitors. We tested 5768 drugs (0-1µM) with diverse targets in NOTCH1 mutant (NOTCH1MUT - HN31, UMSCC22A, PCI-15B) HNSCC cell lines and copanlisib acquired resistant (CAR) HN31 clones. We determined drug efficacy using two metrics-area over the curve lethal dose (AOC_LD>0, cytotoxic) and area under the growth curve (AUC_GRI<0.9, cytostatic). These metrics are more robust than IC50 values as they use the normalized growth rate inhibition curve and avoid the confounding effect of the rate of cell division. Of 306 drug classes, 100 were effective with at least one drug being cytotoxic or cytostatic in at least one cell line. PLK inhibitors were the most effective class of drugs against NOTCH1MUT HNSCC cell lines (87% effective - 12 cytotoxic, 2 cytostatic, 2 ineffective). We further tested the PLK1-specific inhibitor onvansertib (0-100nM) combined with pan-PI3K inhibitor copanlisib (0-200nM) or dual inhibitor bimiralisib (0-1μM). We observed robust decreases in cell numbers at very low drug concentrations (50nM) with the combinations. We validated these results in vitro in NOTCH1MUT, NOTCH1WT, CAR NOTCH1MUT HNSCC models, and HEK293 by using independent approaches to test for apoptosis. A significant increase in cleaved PARP and cleaved caspase 3, and Annexin V/PI staining (>2x), was evident when PI3K and PLK1 were concurrently inactivated as compared to single agent treatment in HNSCC models. Furthermore, HEK293 cells were unaffected at these doses. We then investigated the role of PLK1 following PI3K inhibition in HNSCC models and found PLK1 protein levels to be downregulated. As PLK1 is downstream of Aurora kinases, we further determined the phospho-PLK1 (p-PLK1) levels in HNSCC models. Interestingly, p-PLK1 levels remained unaltered in NOTCH1WT and CAR NOTCH1MUT cells despite total protein level depletion. However, p-PLK1 levels drastically decreased in NOTCH1MUT HNSCC cells. This finding could explain the importance of PLK1 inactivation in addition to PI3K inhibition as a requirement for increased cell death in HNSCC models. We will further validate this combination in vivo to determine the effect of combined PI3K and PLK1 inhibition on tumor growth and survival. These novel findings may lead to the development of a better therapeutic approach for NOTCH1MUT HNSCC and for patients who develop acquired resistance to targeted therapies. Citation Format: Pooja A. Shah, Tuhina Mazumdar, Reid T. Powell, Li Shen, Jing Wang, Clifford C. Stephen, Mitchell J. Frederick, Faye M. Johnson. Concurrent inactivation of PI3K and PLK1 is synergistic and overcomes acquired resistance to PI3K inhibitors in NOTCH1MUT HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2847.
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Tauchi, Tetsuzo, Daigo Akahane, Kousuke Nunoda, Seiichi Okabe, John Pollard, and Kazuma Ohyashiki. "Combined Effects of a Pan-Aurora Kinase Inhibitor MK-0457 and Dasatinib Against T315I Mutant Form of BCR-ABL: In Vitro and In Vivo Studies." Blood 110, no. 11 (November 16, 2007): 805. http://dx.doi.org/10.1182/blood.v110.11.805.805.
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Abstract MK-0457 is a pan-Aurora kinase inhibitor that has firstly shown clinical activity in BCR-ABL positive leukemia patients harboring the T315I mutation. Combining MK-0457 with ABL kinase inhibitors may provide several advantages, including enhanced efficacy and the potential to reduce the emergence of new resistant mutations. In the present study, we investigated the combined effects of MK-0457 and dasatinib in T315I mutant-expressing cells. Co-treatment with MK-0457and dasatinib caused significantly more inhibition of colony growth of primary leukemia cells and BaF3 cells expressing T315I BCR-ABL than either drug alone. In contrast, we did not observe the enhanced effects of MK-0457 and imatinib in T315I BCR-ABL-expressing cells. Treatment with 5 μM of MK-0457 for 48 hrs induced apoptosis in T315I BCR-ABL BaF3 cells, whereas, exposure to combination with 1.0 μM of MK-0457 and 50 nM of dasatinib exerted enhanced apoptotic effect. Combined treatment with MK-0457 and dasatinib also associated with more PARP cleavage, which is due to increased activation of caspase-3 and caspase-9 during apoptosis. Following co-treatment with MK-0457 and dasatinib caused more attenuation of the level of phospho-Stat5 and the downstream signal transducer, including Bcl-XL, Mcl-1, and cyclin D1. We also observed that combined treatment with MK-0457 and dasatinib enhanced the activation of p38MAP kinase and MAPKAP Kinase-2 (MK2). Pretreatment with p38MAP kinase or MP2 siRNA in T315I BCR-ABL BaF3 cells reduced the induction of apoptosis after MK-0457 and dasatinib exposure. These results suggest that p38MAP kinase and MK2 have a critical role for the induction of apoptosis after MK-0457 and dasatinib exposure. To assess the mechanism of combination effect between MK-0457 and dasatinib on T315I BCR-ABL-expressing cells, we used RNA interference to determine whether reduction of SRC-family kinases affected the growth inhibition. BaF3 cells expressing T315I BCR-ABL pretreated with Lyn or Hck siRNA showed enhanced growth inhibition with MK-0457. These results demonstrate that the enhanced growth inhibition by MK-0457 and dasatinib in T315I-expressing cells may be mediated by Lyn and Hck. To assess the in vivo efficacy of MK-0457 and dasatinib, athymic nude mice were injected i.v. with BaF3 cells expressing T315I mutant form of BCR-ABL. 24 hrs after injection, the mice were divided four groups (5 mice per group), with each group receiving either vehicle, MK-0457 (30mg/kg b.i.d.; ip for 5 days), dasatinib (10mg/kg q.d.; po for five days), MK-0457 (30mg/kg b.i.d.; ip for 5 days) + dasatinib (10mg/kg q.d.; po for five days). The treatment was repeated in every 3 weeks. The vehicle or dasatinib-treated mice died of a condition resembling acute leukemia by 28 days; the MK-0457 only-treated mice survived more than 56 days, and the combination of MK-0457 + dasatinib -treated mice survived more than 70 days. Histopathologic analysis of vehicle or dasatinib-treated mice revealed infiltration of the spleen and bone marrow with leukemic blasts. In contrast, histopathologic analysis of organs from MK-0457 plus dasatinib-treated mice demonstrated normal tissue architecture and no evidence of residual leukemia. Taken together, the present study shows that the combination of MK-0457 and dasatinib exhibits a desirable therapeutic index that can reduce the in vivo growth of T315I mutant form of BCR-ABL-expressing cells in an efficacious manner.
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Lawasut, Panisinee, Hannah M. Jacobs, Jake E. Delmore, Joseph Negri, Douglas W. McMillin, Ellen L. Weisberg, James D. Griffin, Paul G. Richardson, Kenneth C. Anderson, and Constantine S. Mitsiades. "In Vitro Anti-Myeloma Activity of the Multitargeted Kinase Inhibitor Midostaurin in the Context of Heterotypic Cocultures of Myeloma Cells with Nonmalignant Microenvironmental Accessory Cells." Blood 118, no. 21 (November 18, 2011): 2923. http://dx.doi.org/10.1182/blood.v118.21.2923.2923.
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Abstract Abstract 2923 Midostaurin (PKC412; Novartis Pharmaceuticals) is a multi-targeted kinase inhibitor currently being evaluated in clinical trials in acute myelogenous leukemia (AML), because of its potent activity in cells expressing mutant FLT3. Prior preclinical studies from our groups have shown that PKC412 has FLT3-independent anti-MM activity, and the effects on AML cells is suppressed by the presence of conditioned media from bone marrow stromal cells (BMSCs), such as the immortalized BMSC line HS-5 (Weisberg et al. Mol Cancer Ther 2007). In this study, we evaluated whether the microenvironment-dependent drug resistance to PKC412 applies to not only AML cells, but also to cells from MM and other FLT3-negative malignant cells. We tested a panel of cells from MM (n=8), FLT-ITDneg AML (n=1), CML (n=2) and breast cancer (n=2) for their response to PKC412 in the presence or absence of BMSCs and other non-malignant accessory cells using tumor cell compartment-specific bioluminescence imaging (CS-BLI), as in our antecedent studies (McMillin et al. Nat Medicine 2010). We also compared the PKC412 response of the aforementioned neoplastic cells when cultured in vitro in the presence or absence of conditioned media (CM) from different types of BMSCs known to confer PKC412 resistance in FLT3-mutant AML cells. Consistent with our previous studies of PKC412 treatment in conventional cultures of MM cells in isolation, we observed that PKC412 exhibits an anti-proliferative effect within the first 24 hrs of treatment, with major reduction of the numbers of viable cells at 48 and 72 hrs. At sub-micromolar doses that did not significantly affect the viability of non-malignant accessory cells tested, PKC412 had similar (or for some MM cell lines had more pronounced) activity against the MM cells, both in the presence and absence of the non-malignant accessory cells tested (HS-5, HS-27a, NIH-3T3 cells with or without transfection with human CD40L, etc.). In contrast, under the same experimental conditions, coculture with either BMSCs or exposure to their conditional media, decreased the response of MM cells to dexamethasone. These results suggested in contrast to the impact on FLT3mut AML, that the anti-MM activity of PKC412 is preserved (and in some cases slightly enhanced) when the MM cells interact with microenvironmental accessory cells and/or their secreted growth/survival factors. To obtain insight on possible mechanistic foundations of these observations, we examined the pattern of kinases inhibited by PKC412 at sub-μM concentrations (using FLT3 and FGFR3, known targets of PKC412 as positive controls). The results of in vitro kinase activity assays showed that PKC412 potently suppresses the aforementioned positive controls, but also exerts >50% inhibitory effect on the in vitro activity of additional kinases such as Akt2, Pim1, GSK3a, PDK1, p70S6K, SRC and Aurora A. Many of these kinases are known to participate in proliferative/anti-apoptotic signaling cascades downstream of cytokine/growth factor receptors or cell adhesion-mediated events triggered during MM–stromal interactions. We therefore conclude that the influence of the tumor microenvironment on the anti-neoplastic effects of PKC412 may be tumor-type dependent. The anti-MM activity of PKC412 is not subject to drug resistance triggered by non-malignant accessory cells, and conversely is occasionally moderately enhanced by these MM-stromal interactions. Mechanistically, this observation may be attributed in part to the multi-targeted nature of this inhibitor and, in particular, its aggregate impact on several kinases known to mediate stroma-induced proliferative and antipoptotic signaling in MM. Disclosures: Griffin: Novartis Pharmaceuticals: Consultancy, Research Funding. Richardson:Millennium: ; Celgene: ; Johnson & Johnson: ; Novartis: ; Bristol Myers Squibb:. Anderson:Celgene: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Mitsiades:EMD Serono: Research Funding; AVEO Pharma: Research Funding; Amgen: Research Funding; OSI Pharmaceuticals: Research Funding; PharmaMar: licensing royalties; Amnis Therapeutics: Consultancy, Honoraria; Centocor: Consultancy, Honoraria; Pharmion: Consultancy, Honoraria; Kosan: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis Pharmaceuticals: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Millennium Pharmaceuticals: Consultancy, Honoraria; Sunesis: Research Funding; Gloucester Pharmaceuticals: Research Funding; Genzyme: Research Funding; Johnson & Johnson: Research Funding.
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Cortes, Jorge, Gail J. Roboz, Hagop Kantarjian, Eric Feldman, Judy Karp, Allyson Pollack, Katrina Sandy, Niranjan Rao, Shiro Akinaga, and Mark Levis. "A Phase I Dose Escalation Study of KW-2449, an Oral Multi-Kinase Inhibitor Against FLT3, Abl, FGFR1 and Aurora in Patients with Relapsed/Refractory AML, Treatment Resistant/Intolerant CML, ALL and MDS." Blood 110, no. 11 (November 16, 2007): 909. http://dx.doi.org/10.1182/blood.v110.11.909.909.
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Abstract Background: Activating mutations of FMS-like tyrosine kinase 3 (FLT3) occur in 30% of patients (pts) with de novo AML and confer a worse prognosis. KW-2449 is an oral multi-kinase inhibitor highly potent against mutant FLT3 (IC50= 1–7 nmol/L) and other tyrosine kinases including FGFR1, TrkA, Abl (including T315I), JAK2, c-KIT, and c-SRC and Aurora A serine tyrosine kinase. Based on the anti-leukemia activity of KW-2449 demonstrated both in vitro and in vivo preclinical leukemia models, KW-2449 is being evaluated in hematologic conditions in the first-in-man study. Methods: The study objectives were to assess the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic effects of KW-2449 in pts with refractory/relapsed AML or treatment resistant/intolerant CML/ALL and MDS. A range of daily doses of KW-2449 (25–500 mg/day) divided into q 12h dosing on 2 treatment schedules (14 days vs. 28 days) with a recovery period of 7–28 days between cycles. Dose limiting toxicity (DLT) and maximally tolerated dose were assessed for the 1st cycle. Serial samples for PK analysis were collected immediately before and after KW-2449 on treatment days 1, 14 and 28. The 28-day schedule was later eliminated. Plasma concentrations of KW-2449 and its active metabolite (M1) were analyzed by LC-MS/MS. A plasma inhibitory activity (PIA) assay [Blood 108(10) 3477–83] for P-FLT3 and P-STAT5 was used to measure FLT3 inhibition. Results: To date, 29 pts (15 female) have been enrolled (median age 60 years; range 25–82) and treated at 5 dose levels: 25, 50, 100, 200, and 300 mg daily. Twenty-five pts had AML and 4 CML (3 with T315I mutation); 24 pts completed at least 1 cycle. KW-2449 was rapidly absorbed and metabolized to M1. Elimination half-lives were 2.8–3.9 h for KW-2449 and 3.8–5.5 h for M1. Plasma levels of M1 were lower on Days 14 and 28 compared to Day 1, suggesting inhibition of this pathway upon multiple dosing. A single DLT of grade 3 pneumonia was reported on 100 mg but no further DLTs were seen in the expanded cohort at that dose or at 200 or 300 mg daily. A total of 33 SAEs were reported of which 6 were considered possibly related (by the Investigator) to KW-2449: dyspnea, pneumonia, atrial fibrillation, cardiac ischemia, ventricular arrhythmia, and pleural effusion. There have been 5 deaths on study (none drug-related): disease progression (2), neutropenic sepsis, infection with renal failure, and pneumonia. Seven pts had stable disease after 1 cycle. Three pts with AML (2 FLT3+) had ≥ 50% reduction in peripheral and/or bone marrow blasts in the 1st cycle. In vivo FLT3 inhibition, as measured directly in patient blasts, correlated with blast reduction. The extent and duration of FLT3 inhibition increased with increases in dose. Conclusions: KW-2449 appears safe and well tolerated at the dose levels evaluated. Transient decreases in peripheral blood and bone marrow blasts have been observed in a few patients justifying continued investigation with this agent. Accrual is ongoing and a different schedule to accommodate the short t1/2 will be explored.
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Bagashev, Asen, Joseph Patrick Loftus, Colin Wakefield, Gerald Wertheim, Christian Hurtz, Martin P. Carroll, Kimberly Stegmaier, Yana Pikman, and Sarah K. Tasian. "Alisertib Synergistically Strengthens the Anti-Leukemia Activity of Venetoclax in TCF3-Hlf B-ALL." Blood 138, Supplement 1 (November 5, 2021): 705. http://dx.doi.org/10.1182/blood-2021-148671.
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Abstract Background: Despite maximally-intensive chemotherapy and stem cell transplantation, survival of patients with the very rare t(17;19)/TCF3-HLF B-acute lymphoblastic leukemia (B-ALL) subtype remains effectively 0%. Prior studies have demonstrated association of the oncogenic TCF3-HLF fusion protein with multi-drug resistance via increased expression of ABC and P-glycoprotein drug efflux transporters, as well as via upregulation of pro-survival Ras and BCL-2 pathways. Preclinical studies and small clinical case series of targeted inhibitor addition to chemotherapy or antibody-based and cellular immunotherapies have aimed to improve outcomes for children with TCF3-HLF ALL. Unfortunately, targeting of these activated pathways with the BCL-2 inhibitor venetoclax or other small molecule inhibitors (SMIs) has been minimally or only transiently effective, suggesting more complex mechanism(s) of chemoresistance. In recent years, many patients with relapsed TCF3-HLF ALL have enrolled on clinical trials of CD19- or CD22-targeted immunotherapies. However, TCF3-HLF ALL frequently harbours deactivating mutations in PAX5, a major B-cell regulator and indispensable CD19 transcription factor, placing immunotherapy-treated patients at higher risk of CD19 antigen-loss relapse. New therapies remain needed to prevent relapse and attempt cure. Methods: We designed an unbiased kinome-wide CRISPR/Cas9 library to identify essential drivers in TCF3-HLF leukemogenesis. We screened the human TCF3-HLF ALL cell line HAL-01 and our TCF3-HLF ALL patient-derived xenograft (PDX) model ALL1807 (Hurtz JCI 2020, Schultz Genome Biol 2021), then validated identified targets using 49 SMIs targeting receptor tyrosine kinases (RTK), MEK signaling, and cell cycle pathways. We selected promising candidate inhibitor pairings with non-overlapping mechanisms of action and assessed for in vitro drug synergy via SynergyFinder analyses. Finally, we assessed the in vivo activity of targeted inhibitors in ALL1807 and two newly established TCF3-HLF ALL PDX models (CPCT-0002, CPCT-0003) created from primary pediatric specimens obtained via the LEAP Consortium (Pikman Cancer Disc 2021). Results: RNA-sequencing of HAL-01 and ALL1807 cells followed by functional protein association (STRING) analysis confirmed a network of significantly upregulated (>3-fold) plasma membrane and cytoplasm components of RTK pathways as well as BCL-2. The intersection of the results of the SMI drug library screen with the top 1% targets identified in CRIPSR/Cas9 screen determined p120-RasGAP and Aurora kinase A (AURKA) as therapeutic targets in TCF3-HLF ALL. In vitro treatment of HAL-01 or ALL1807 cells with the RasGAP inhibitor, pluripotin, or the AURKA inhibitor, alisertib, across a range of concentrations demonstrated robust anti-ALL activity. AURKA and RasGAP co-immunoprecipitated and this protein complex was disrupted with alisertib or pluripotin treatment. The AURKB inhibitor barisertib had minimal activity against TCF3-HLF ALL cells, confirming preferential dependency of these cells upon AURKA. Treatment of TCF3-HLF ALL cells with the BCL-2i venetoclax did not disrupt the AURKA/RasGAP complex, suggesting its different mechanism of action and potential for combinatorial drug therapy. Next, we found that alisertib and venetoclax synergistically killed TCF3-HLF ALL cells. Finally, we observed superior inhibition of in vivo leukemia with dual AURKA and BCL-2 inhibitor treatment of three TCF3-HLF ALL PDX models compared to single-agent alisertib or venetoclax (Figure 1). Conclusions: We identified AURKA as a critical new driver in TCF3-HLF ALL via orthogonal genetic and functional assays and confirmed prior observations of BCL-2 dependency in our models. We validated these key targets via in vitro and in vivo pharmacologic inhibition studies with drug synergy detected with combined alisertib and venetoclax in human TCF3-HLF ALL cell lines and PDX models. We posit that dual AURKA and BCL-2 inhibition is a clinically-pragmatic and potentially effective therapeutic strategy for patients with this rare, but highly fatal, leukemia subtype that merits formal clinical investigation. Figure 1 Figure 1. Disclosures Carroll: Incyte Pharmaceuticals: Research Funding; Janssen Pharmaceutical: Consultancy. Stegmaier: Auron Therapeutics, Kronos Bio, AstraZeneca, Novartis Institute of Biomedical Research: Consultancy, Research Funding. Tasian: Incyte Corporation: Research Funding; Gilead Sciences: Research Funding; Kura Oncology: Consultancy; Aleta Biotherapeutics: Consultancy.
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Delmore, Jake, David N. Cervi, Douglas McMillin, Efstathios Kastritis, Jana Jakubikova, Melissa G. Ooi, Steffen Klippel, et al. "The Transcriptional Signature of Kinases Inhibited by the Multi-Targeted Kinase Inhibitor AS703569 Is Associated with Clinical Outcome in Multiple Myeloma (MM): Anti-MM Activity of AS703569 in Preclinical Studies." Blood 114, no. 22 (November 20, 2009): 730. http://dx.doi.org/10.1182/blood.v114.22.730.730.
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Abstract Abstract 730 Multi-targeted kinase inhibitors, when associated with manageable toxicity, offer the therapeutically desirable option of targeting, through a single chemical entity, several pathways that may contribute to the complexity and heterogeneity of molecular lesions harbored by neoplasias such as multiple myeloma (MM). However, intractable questions often emerge while prioritizing for preclinical studies different multi-targeted agents with extensive and/or only partially overlapping of sets of known targets. We have hypothesized that the potential therapeutic relevance of a multi-targeted inhibitor may be reflected on the prognostic relevance of its targets' transcriptional signature. We applied this concept in the case of the orally bioavailable multi-targeted kinase inhibitor AS703569, which targets (with IC50 in low nM range) all 3 Aurora kinase (AK) isoforms as well as various other kinases (e.g. cSRC, FGFR1, Flt3, Fyn, Lyn, Rsk1-3, Yes, Axl, et.c.) and evaluated the transcriptional signature of AS703569 kinase targets (with IC50 <10 nM) in MM cells of patients receiving Bortezomib as part of Phase II/III trials (specifically SUMMIT/APEX). We observed that patients with high transcriptional signature of AS703569 targets had inferior progression-free and overall survival (p=0.005 and p=0.012, log-rank test) and also validated that, in a study of tandem autologous transplant, a subset of patients with high levels of this AS703569 target transcriptional signature also have inferior overall survival (p=0.032, log-rank test) compared to cases with low levels of the signature. These observations supported the notion that the kinome space targeted by AS703569 is enriched for targets associated with adverse clinical outcome in MM. In preclinical assays, we observed that AS703569 decreased the viability of MM cell lines and primary CD138+ MM tumor cells in a time- and dose-dependent manner, with IC50 values <50 nM for the majority of cell lines tested; and without evidence of cross-resistance with established anti-MM agents. Combinations of AS703569 with dexamethasone, doxorubicin, or bortezomib did not exhibit antagonism, suggesting that AS703569 can be incorporated in regimens with these established anti-MM drug classes. Interestingly, in vitro compartment-specific bioluminescence imaging (CS-BLI) assays showed that against MM cells which respond to stromal cells with increased proliferation and survival, the anti-MM activity of AS703569 is more pronounced when these MM cells are co-cultured with bone marrow stromal cells than in conventional cultures in isolation. This indicated that AS703569 is capable of overcoming the protective effects that BMSCs confer to MM tumor cells and prompted in vivo validation studies in our orthotopic SCID/NOD model of diffuse MM bone lesions established by i.v. injection of MM-1S-GFP/Luc cells monitored by whole body bioluminescence imaging. AS703569 (50 mg/kg p.o. once weekly)-treated mice had longer overall survival than vehicle-treated mice (median 50.0 days, 95% C.I. 40.3-59.7 days vs. 39.0 days, 95% C.I., 35.4-42.6 days, p=0.019, log-rank test). An alternative schedule of AS703569 at 16.7 mg/kg 3 times/week also resulted in longer overall survival (median 54.0 days, 95% C.I. 33.2-74.8 days, p=0.023, log-rank test). These data indicate that AS703569 exhibits anti-MM activity in vitro and in orthotopic in vivo MM models, and suggests that this multi-targeted inhibitor merits considerations for further preclinical studies, as well as potential clinical studies in MM, especially given the otherwise adverse outcome associated with the inhibitor's target transcriptional signature. Disclosures: Laubach: Novartis: Consultancy, Honoraria. Rastelli:EMD Serono: Employment. Clark:EMD Serono: Employment. Sarno:EMD Serono: Employment. Richardson:Millenium: (Speakers' Bureau up to 7/1/09), Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: (Speakers' Bureau up to 7/1/09), Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Anderson:Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mitsiades:Millennium: Consultancy, Honoraria; Novartis : Consultancy, Honoraria; Bristol-Myers Squibb : Consultancy, Honoraria; Merck & Co: Consultancy, Honoraria; Kosan Pharmaceuticals: Consultancy, Honoraria; Pharmion: Consultancy, Honoraria; PharmaMar: Patents & Royalties; Amgen: Research Funding; AVEO Pharma: Research Funding; EMD Serono : Research Funding; Sunesis Pharmaceuticals: Research Funding.
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Mastrogamvraki, Natalia, and Apostolos Zaravinos. "Signatures of co-deregulated genes and their transcriptional regulators in colorectal cancer." npj Systems Biology and Applications 6, no. 1 (July 31, 2020). http://dx.doi.org/10.1038/s41540-020-00144-8.
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Abstract The deregulated genes in colorectal cancer (CRC) vary significantly across different studies. Thus, a systems biology approach is needed to identify the co-deregulated genes (co-DEGs), explore their molecular networks, and spot the major hub proteins within these networks. We reanalyzed 19 GEO gene expression profiles to identify and annotate CRC versus normal signatures, single-gene perturbation, and single-drug perturbation signatures. We identified the co-DEGs across different studies, their upstream regulating kinases and transcription factors (TFs). Connectivity Map was used to identify likely repurposing drugs against CRC within each group. The functional changes of the co-upregulated genes in the first category were mainly associated with negative regulation of transforming growth factor β production and glomerular epithelial cell differentiation; whereas the co-downregulated genes were enriched in cotranslational protein targeting to the membrane. We identified 17 hub proteins across the co-upregulated genes and 18 hub proteins across the co-downregulated genes, composed of well-known TFs (MYC, TCF3, PML) and kinases (CSNK2A1, CDK1/4, MAPK14), and validated most of them using GEPIA2 and HPA, but also through two signature gene lists composed of the co-up and co-downregulated genes. We further identified a list of repurposing drugs that can potentially target the co-DEGs in CRC, including camptothecin, neostigmine bromide, emetine, remoxipride, cephaeline, thioridazine, and omeprazole. Similar analyses were performed in the co-DEG signatures in single-gene or drug perturbation experiments in CRC. MYC, PML, CDKs, CSNK2A1, and MAPKs were common hub proteins among all studies. Overall, we identified the critical genes in CRC and we propose repurposing drugs that could be used against them.
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Patnaik, Sunil Kumar, Akey Krishna Swaroop, Mudavath Ravi Naik, Jubie Selvaraj, and Moola Joghee Nanjan Chandrasekar. "Repurposing of FDA Approved Drugs and Neuropep peptides as Anticancer Agents Against ErbB1 and ErbB2." Drug Research, April 17, 2023. http://dx.doi.org/10.1055/a-2030-4078.
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AbstractErbB1 and ErbB2 are the most important biological targets in cancer drug discovery and development of dual inhibitors for the cancer therapy. FDA approved drugs and Neuropep peptides were used to fit into the ATP binding site of the tyrosine kinases; ErbB1 and ErbB2 proteins. Cytoscape, iGEMDOCK, HPEPDOCK and DataWarrior softwares were used to study the role of these agents as anticancer drugs. Eleven FDA approved drugs and eleven Neuropep peptides showed the strongest 2D interactions and significant binding energy with the proteins. Invitro MTT anticancer assay revealed that, the test compounds, peptide YSFGL and doxorubicin showed significant IC50 value (µM) of 26.417±0.660 and 7.675±0.278 respectively which are compared with the lapatinib standard IC50 value (µM) of 2.380±0.357 against A549 cells and IC50 value (µM) of 39.047±0.770 and 8.313±0.435 respectively which are compared with the lapatinib standard IC50 value (µM) of 3.026±0.180 against MDA-MB-231 cells.