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1
Deininger, Michael. "Targeting Tyrosine Kinase Receptors." Blood 122, no. 21 (November 15, 2013): SCI—25—SCI—25. http://dx.doi.org/10.1182/blood.v122.21.sci-25.sci-25.
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Abstract Protein tyrosine kinases (PTKs) regulate cell growth and other key functions. Constitutive PTK activation by somatic mutations, overexpression, or abnormal upstream signaling is characteristic of many cancers, including hematologic malignancies, providing a rationale for therapeutically targeting PTKs with small molecules. Imatinib, an ATP-competitive inhibitor of BCR-ABL1, the PTK causal to chronic myeloid leukemia (CML), established a paradigm for tyrosine kinase inhibitors (TKIs) as cancer therapeutics. Although a relatively weak inhibitor, imatinib is effective in most patients with chronic phase CML (CML-CP), while responses are transient in blastic phase (CML-BP). Point mutations in the BCR-ABL1 kinase domain have emerged as a major mechanism of drug resistance. The more potent second-generation TKIs – dasatinib, nilotinib, and bosutinib – induce deeper and faster responses and are active against many imatinib-resistant mutants, with the exception of T315I in the gatekeeper position of the catalytic site. This problem was addressed with ponatinib, a third-generation TKI covering all single BCR-ABL1 mutants, including T315I. Ponatinib has excellent clinical activity in CML-CP patients who failed other TKIs, while responses in CML-BP are short-lived. Some patients fail ponatinib due to BCR-ABL1 compound mutations, suggesting even third-generation TKIs cannot completely prevent mutational escape by the disease-initiating kinase. Another unsolved problem is that TKIs fail to efficiently target CML stem cells, leading to recurrence of active leukemia upon discontinuation. Despite these shortcomings, TKIs have completely changed the face of CML. Unfortunately, repeating this success in other hematologic malignancies has been challenging, likely reflecting differences in disease biology as much as suboptimal design of early compounds. CML-CP represents one extreme of the spectrum, where a single genetic lesion is sufficient to produce the phenotype and the hierarchy of hematopoietic differentiation is maintained. The situation is different in acute myeloid leukemia (AML) with activating FLT3 mutations. Not only these AML cases have mutations in other genes, they typically acquire FLT3 mutations late during disease evolution, implying that the disease-initiating clone will be impervious to FLT3 inhibition. Progress has been made through successive development of more potent TKIs with improved pharmacology, leading to quizartinib. It is clear, however, that FLT3 inhibitors cannot be used as single agents if there is a curative intent and the same may be true for JAK2 inhibitors in myelofibrosis. The first approved JAK2 inhibitor, ruxolitinib, dramatically improves symptoms, but has yet to demonstrate a significant impact on the malignant clone and is certainly not curative. It remains to be seen whether this reflects the fact that JAK2 activation is not the disease–initiating event, lack of inhibitor specificity towards the mutant JAK2 kinase, or other undesirable off-target effects that may be overcome with improved drugs. A completely new chapter was opened with ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase (BTK), for the treatment of chronic lymphocytic leukemia (CLL). BTK is essential for signal transduction from the B-cell receptor (BCR). No activating mutations in BTK have been identified in lymphoma or CLL, but constitutive BCR signaling is critical to CLL cell survival in the microenvironment. Early studies show excellent clinical activity in patients with advanced CLL, although many responses are incomplete; much like the imatinib responses in late CML-CP. Ibrutinib may have a similarly profound effect upon CLL as imatinib on CML, but perhaps also similar limitations, such as the inability to eradicate residual leukemia; this of course needs to be tested in frontline studies. TKIs have had a significant albeit uneven impact upon treatment paradigms in hematologic malignancies. Future progress will involve optimizing compounds in terms of potency, selectivity, and pharmacokinetics. Allosteric inhibitors may add to the armamentarium. From the target perspective, it is likely that most activated kinase alleles have been discovered and the focus should shift to identification of disease-critical unmutated kinases. Lastly, identifying synthetically lethal inhibitor combinations will be critical to fully exploit the potential of TKI therapy. Disclosures: Deininger: BMS: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; ARIAD: Consultancy, Membership on an entity’s Board of Directors or advisory committees; NOVARTIS: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; CELGENE: Research Funding; GENZYME: Research Funding; INCYTE: Consultancy, Membership on an entity’s Board of Directors or advisory committees; GILEAD: Research Funding.
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Chen, Jin-Shuen, Li-Chien Chang, Shyh-Jer Huang, and Chao-Wen Cheng. "Targeting Spleen Tyrosine Kinase-Bruton’s Tyrosine Kinase Axis for Immunologically Mediated Glomerulonephritis." BioMed Research International 2014 (2014): 1–6. http://dx.doi.org/10.1155/2014/814869.
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The importance of B-cell activation and immune complex-mediated Fc-receptor activation in the pathogenesis of immunologically mediated glomerulonephritis has long been recognized. The two nonreceptor tyrosine kinases, spleen tyrosine kinase (Syk) and Bruton’s tyrosine kinase (Btk), are primarily expressed by hematopoietic cells, and participate in B-cell-receptor- and Fc-receptor-mediated activation. Pharmacological inhibitors of Syk or Btk are undergoing preclinical development and clinical trials for several immune diseases; and Syk inhibitors have been shown to reduce disease activity in rheumatoid arthritis patients. However, the clinical therapeutic efficacies of these inhibitors in glomerulonephritis have not been evaluated. Herein, we review recent studies of Syk and Btk inhibitors in several experimental primary and secondary glomerulonephritis models. These inhibitors suppressed development of glomerular injury, and also ameliorated established kidney disease. Thus, targeting Syk and Btk signaling pathways is a potential therapeutic strategy for glomerulonephritis, and further evaluation is recommended.
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Forster, Michael, Xiaojun Julia Liang, Martin Schröder, Stefan Gerstenecker, Apirat Chaikuad, Stefan Knapp, Stefan Laufer, and Matthias Gehringer. "Discovery of a Novel Class of Covalent Dual Inhibitors Targeting the Protein Kinases BMX and BTK." International Journal of Molecular Sciences 21, no. 23 (December 4, 2020): 9269. http://dx.doi.org/10.3390/ijms21239269.
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The nonreceptor tyrosine TEC kinases are key regulators of the immune system and play a crucial role in the pathogenesis of diverse hematological malignancies. In contrast to the substantial efforts in inhibitor development for Bruton’s tyrosine kinase (BTK), specific inhibitors of the other TEC kinases, including the bone marrow tyrosine kinase on chromosome X (BMX), remain sparse. Here we present a novel class of dual BMX/BTK inhibitors, which were designed from irreversible inhibitors of Janus kinase (JAK) 3 targeting a cysteine located within the solvent-exposed front region of the ATP binding pocket. Structure-guided design exploiting the differences in the gatekeeper residues enabled the achievement of high selectivity over JAK3 and certain other kinases harboring a sterically demanding residue at this position. The most active compounds inhibited BMX and BTK with apparent IC50 values in the single digit nanomolar range or below showing moderate selectivity within the TEC family and potent cellular target engagement. These compounds represent an important first step towards selective chemical probes for the protein kinase BMX.
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Manzo, Lawaly Maman, Moudirat Lawaly, and Lui YU. "Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-small cell lung cancer." Indian Journal of Pharmaceutical and Biological Research 3, no. 02 (June 30, 2015): 81–87. http://dx.doi.org/10.30750/ijpbr.3.2.10.
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Aberrant increased expression and activation of receptor tyrosine kinases occur frequently in human carcinomas. Several small molecules targeting receptor tyrosine kinases, which have crucial roles in the growth factor signaling that promote tumor progression in various malignancies, including non-small cell lung cancer (NSCLC), are currently in clinical development. Therapeutic strategies include inhibition of growth factor tyrosine kinase function. Drugs of this type include those that target the epidermal growth factor receptor tyrosine kinase, those that target vascular endothelial growth factor receptors tyrosine kinase and those that target anaplastic lymphoma receptor tyrosine kinase. In this review we first discuss the role of receptor tyrosine kinases in human malignancies, and focus on discussing the potential use of epidermal growth factor receptor tyrosine kinase inhibitors and the vascular endothelial growth factor receptors tyrosine kinase inhibitors in NSCLC. In addition, we discuss the contribution of growth factor receptor tyrosine kinase inhibitors to the clinically observed resistance, and toxicity.
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Cher, Chae Yin, Cheuk Him Man, Stephen S. Y. Lam, Eric S. K. Ho, Nelson K. L. Ng, Marie-Anne Hospital, Jerome Tamburini, and Anskar Y. H. Leung. "Targeting Polo-like Kinase in Acute Myeloid Leukemia." Blood 124, no. 21 (December 6, 2014): 2234. http://dx.doi.org/10.1182/blood.v124.21.2234.2234.
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Abstract Acute myeloid leukemia (AML) carrying fms-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) is associated with poor prognosis when treated with conventional chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). Despite much interest in tyrosine kinase inhibitor (TKI) targeting FLT3 activation, drug resistance is invariable and acquisition of secondary point mutation in the tyrosine kinase domain (TKD) of FLT3 was frequently reported. We have shown that genes encoding cell cycle regulators including polo-like kinase 1 (PLK1), cell division cycle 25 homolog A (CDC25A), cyclin B2 (CCNB2), and cyclin E1 (CCNE1) were up-regulated in sorafenib-resistant primary AML samples. In particular, PLK1, a member of the polo-like kinase family, has been found to express at several checkpoints critical for cell cycle progression. PLK1 inhibitors have recently been exploited for the treatment of both solid organ and haematological cancers. We hypothesized that aberrant cell cycle progression mediated by increased PLK1 expression might confer survival advantage to drug resistant AML cells and be targetable by PLK1 inhibition. In vitro treatment with PLK1 inhibitors volasertib and BI 2536 significantly inhibited the growth of 8 AML cell lines (KG-1, ML2, MOLM-13, MV4-11, Kasumi-1, NB4, THP-1 and OCI-AML3) with IC50 (all in nM) ranging from 48.7 - 98.4 (volasertib) and 35.1 - 81.6 (BI 2536). The growth inhibitory effects of PLK1 inhibition on two FLT3-ITD+ cell lines, MOLM-13 and MV411, correlated with induction of apoptosis and cell cycle arrest at G2/M phase. Moreover, both PLK1 inhibitors significantly suppressed the growth of a sorafenib resistant MOLM-13R cell line and sorafenib naïve MOLM-13N cell line. Introduction of FLT3-ITD alone or FLT3-ITD and TKD double mutations into Ba/F3 cell lines sensitized them to the growth inhibitory effects of PLK1 inhibitors. Primary FLT3-ITD+ AML cells obtained from patients at TKI resistance were shown to be more sensitive to PLK1 inhibitors than those obtained before treatment. The results suggested that the TKI resistant clones could be effectively targeted by PLK1 inhibition, providing an insight to the design of combination treatment with FLT3 inhibitors in FLT3-ITD+ AML. Disclosures No relevant conflicts of interest to declare.
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Grimminger, Friedrich, Ralph T. Schermuly, and Hossein A. Ghofrani. "Targeting non-malignant disorders with tyrosine kinase inhibitors." Nature Reviews Drug Discovery 9, no. 12 (December 2010): 956–70. http://dx.doi.org/10.1038/nrd3297.
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Pasquet, Jean-Max, Romain Gioia, Claire Drullion, Valerie Lagarde, Cedric Leroy, Serge Roche, Bruno Cardinaud, and Francois-Xavier Mahon. "Tyrosine Kinase Proteins profiling of Nilotinib Resistant Chronic Myelogenous Leukemia Cells Unravels a Tyrosine Kinase-Mediated Bypass." Blood 114, no. 22 (November 20, 2009): 2175. http://dx.doi.org/10.1182/blood.v114.22.2175.2175.
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Abstract Abstract 2175 Poster Board II-152 Targeting the tyrosine kinase activity of Bcr-Abl is an attractive therapeutic strategy in Chronic Myeloid Leukemia (CML) and in Bcr-Abl positive Acute Lymphoblastic Leukemia. Whereas imatinib, a selective inhibitor of Bcr-Abl tyrosine kinase, is now used in frontline therapy for CML, second generation inhibitors such as nilotinib or dasatinib have been developed for the treatment of imatinib-resistant or –intolerant disease. We have shown that one of the mechanisms of resistance to nilotinib is an increasing expression of the p53/56 Lyn kinase, both at mRNA and protein level in cell lines. This result was confirmed in vivo in nilotinib-resistant CML patients (Mahon et al. Cancer Res., 2008, 68(23):9809-16.). To elucidate Lyn mediated-nilotinib resistance, a phosphoproteomic study was performed by Stable Isotope Labelling with Amino acid in Cell culture (SILAC) which highlights the potential role of downstream tyrosine kinases. Among different candidate proteinsThe Spleen tyrosine kinase Syk and the UFO family receptor tyrosine kinase Axl were the most relevant in the nilotinib resistant cell line as compared to the sensitive counterpart. Syk hyperphosphorylation was confirmed in the nilotinib resistant cell line using western blot at least on tyrosine residues Y323 and Y525/526, two critical tyrosine residues respectively involved in Lyn-mediated Syk phosphorylation and autophosphorylation-associated Syk activation. Lyn interacts with Syk as detected in Syk immunoprecipitates in nilotinib resistant cells. Furthermore, Syk-Lyn interaction is inhibited by dasatinib suggesting the requirement of Lyn kinase activity and Syk phosphorylation. Targeting Syk expression in nilotinib resistant cells by siRNA or tyrosine kinase activity by pharmacological inhibitors leads respectively to a partial (35%) or to a full restoration of nilotinib sensitivity. Moreover, the identification of Axl by SILAC is correlated to a 9 fold increase of its level of expression in the resistant cell line and the inhibition of Axl tyrosine kinase activity decreases proliferation of both nilotinib sensitive and resistant CML cells. All together these results disclose a new pathway for tyrosine kinase inhibitors resistance in CML involving at least the two Lyn downstream tyrosine kinases Syk and Axl. Disclosures: Mahon: Amgen: Honoraria; Novartis Pharma: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria.
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Sakle, Nikhil S., Shweta A. More, Sachin A. Dhawale, and Santosh N. Mokale. "Targeting Small Molecule Tyrosine Kinases by Polyphenols: New Move Towards Anti-tumor Drug Discovery." Current Drug Discovery Technologies 17, no. 5 (December 23, 2020): 585–615. http://dx.doi.org/10.2174/1570163816666190808120843.
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Background: Cancer is a complex disease involving genetic and epigenetic alteration that allows cells to escape normal homeostasis. Kinases play a crucial role in signaling pathways that regulate cell functions. Deregulation of kinases leads to a variety of pathological changes, activating cancer cell proliferation and metastases. The molecular mechanism of cancer is complex and the dysregulation of tyrosine kinases like Anaplastic Lymphoma Kinase (ALK), Bcr-Abl (Fusion gene found in patient with Chronic Myelogenous Leukemia (CML), JAK (Janus Activated Kinase), Src Family Kinases (SFKs), ALK (Anaplastic lymphoma Kinase), c-MET (Mesenchymal- Epithelial Transition), EGFR (Epidermal Growth Factor receptor), PDGFR (Platelet-Derived Growth Factor Receptor), RET (Rearranged during Transfection) and VEGFR (Vascular Endothelial Growth Factor Receptor) plays major role in the process of carcinogenesis. Recently, kinase inhibitors have overcome many problems of traditional cancer chemotherapy as they effectively separate out normal, non-cancer cells as well as rapidly multiplying cancer cells. Methods: Electronic databases were searched to explore the small molecule tyrosine kinases by polyphenols with the help of docking study (Glide-7.6 program interfaced with Maestro-v11.3 of Schrödinger 2017) to show the binding energies of polyphenols inhibitor with different tyrosine kinases in order to differentiate between the targets. Results: From the literature survey, it was observed that the number of polyphenols derived from natural sources alters the expression and signaling cascade of tyrosine kinase in various tumor models. Therefore, the development of polyphenols as a tyrosine kinase inhibitor against targeted proteins is regarded as an upcoming trend for chemoprevention. Conclusion: In this review, we have discussed the role of polyphenols as chemoreceptive which will help in future for the development and discovery of novel semisynthetic anticancer agents coupled with polyphenols.
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van der Kuip, Heiko, Lara Wohlbold, Carsten Oetzel, Matthias Schwab, and Walter E. Aulitzky. "Mechanisms of Clinical Resistance to Small Molecule Tyrosine Kinase Inhibitors Targeting Oncogenic Tyrosine Kinases." American Journal of PharmacoGenomics 5, no. 2 (2005): 101–12. http://dx.doi.org/10.2165/00129785-200505020-00003.
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Shojaee, Seyedmehdi, Maike Buchner, Huimin Geng, Bolland Silvia, Phillip Koeffler, and Markus Muschen. "Targeting Inhibitory Phosphatases in Tyrosine Kinase-Driven Leukemias." Blood 118, no. 21 (November 18, 2011): 1382. http://dx.doi.org/10.1182/blood.v118.21.1382.1382.
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Abstract Abstract 1382 Background: Current therapy approaches for tyrosine kinase-driven leukemias including Ph+ ALL and CML are almost entirely focused on the development of more potent tyrosine kinase inhibitors (TKI) with the goal to reduce oncogenic signaling below a minimum threshold that is required for the survival of leukemia cells. Studying regulators of BCR-ABL1 kinase signaling strength, we found that three key inhibitory phosphatases (INPP5D/SHIP1, PTEN and PTPN6/SHP1) are expressed at high levels in Ph+ ALL and CML cells. Both INPP5D and PTEN dephosphorylate phosphatidylinositol-3,4,5-trisphosphate, as 5- and 3-phosphatases, respectively. Thereby, both INPP5D and PTEN negatively regulate PI3K/PI5K- and AKT-mediated activation signals. Like INPP5D, PTPN6 is recruited to ITIM motifs in the cytoplasmic tails of inhibitory surface recepotors and negatively regulates activation signals from tyrosine kinases and activating receptors. Results: We hypothesized that Cre-mediated inducible deletion of INPP5D, PTEN and PTPN6 will result in increased oncogenic signaling downstream of BCR-ABL1 and induce blast crisis-transformation of CML and a more aggressive form of Ph+ALL-like leukemia. Surprisingly, however, genetic deletion of INPP5D, PTEN and PTPN6 resulted in drastic upregulation of reactive oxygen species (ROS), accumulation of Arf, p53 and p21, cellular senescence and subsequent cell death of leukemia cells. The deleterious effects of inducible deletion of INPP5D, PTEN and PTPN6 were comparatively mild in CML and drastic in Ph+ ALL-like leukemia Studying BCR-ABL1-transformed Inpp5dfl/fl Ptenfl/fl and Ptpn6fl/fl leukemia cells in vivo, we observed that induction of Cre-mediated deletion resulted in rapid leukemia regression and “cure” of leukemia transplant recipient mice. Pharmacological targeting inhibitory phosphatases for the treatment of leukemia seems counter intuitive because it represents effectively the opposite of current TKI-based therapies. Small molecule inhibition of Pten using the compound VO-OHpic effectively killed patient-derived leukemia cells carrying the T315I mutant BCR-ABL1. Based on these findings, we propose that pharmacological blockade of inhibitory phosphatases represents a powerful means to induce leukemia cell death owing to excessive oncogene signaling. In this case, oncogenic tyrosine kinase signaling is increased above a maximum tolerable threshold, and leukemia cells die because of excessive oxidative stress. Normal cells lacking the BCR-ABL1 oncogene are spared because they are less dependent on inhibitory signaling molecules to counterbalance. According to our concept, tyrosine kinase-driven leukemia cells can only thrive within a certain “comfort zone” of signal strength. Both attenuation below and exaggeration above this “comfort zone” of signal strength results in cell death. If validated, our approach of phosphatase-inhibition will lead to the discovery and development of multiple new targets for therapy and will significantly broaden currently available treatment options for blast crisis CML and Ph+ ALL. Disclosures: No relevant conflicts of interest to declare.
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Dassonville, Olivier, Alexandre Bozec, Jean Louis Fischel, and Gerard Milano. "EGFR targeting therapies: Monoclonal antibodies versus tyrosine kinase inhibitors." Critical Reviews in Oncology/Hematology 62, no. 1 (April 2007): 53–61. http://dx.doi.org/10.1016/j.critrevonc.2006.12.008.
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Lipsky, Andrew, and Nicole Lamanna. "Managing toxicities of Bruton tyrosine kinase inhibitors." Hematology 2020, no. 1 (December 4, 2020): 336–45. http://dx.doi.org/10.1182/hematology.2020000118.
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Abstract Inhibition of Bruton’s tyrosine kinase (BTK) has revolutionized the treatment landscape for patients with chronic lymphocytic leukemia (CLL). By targeting this critical kinase in proximal B-cell receptor signaling, BTK inhibitors (BTKis) impair cell proliferation, migration, and activation of NF-κB. Clinically, because indefinite inhibition is a mainstay of therapy, there is an extended period of exposure in which adverse effects can develop. Given the impressive efficacy and activity of BTKis in the treatment of patients with CLL, appropriate management of treatment-emergent adverse events (AEs) is of paramount importance. Here we review the BTKi landscape and present the available toxicity and safety data for each agent. The long-term toxicity profile of ibrutinib, a first-in-class inhibitor, is well characterized and includes a clinically significant incidence of cardiac arrhythmias, bleeding, infection, diarrhea, arthralgias, and hypertension. Acalabrutinib, the initial second-generation BTKi to earn approval from the US Food and Drug Administration, demonstrates improved kinase selectivity for BTK, with commonly observed adverse reactions including infection, headache, and diarrhea. Mediated by both on-target inhibition of BTK and variable off-target inhibition of other kinases including interleukin-2–inducible T-cell kinase (ITK), tyrosine-protein kinase (TEC), and endothelial growth factor receptor (EGFR), the toxicity profile of BTKis is closely linked to their pattern of kinase binding. Other emerging BTKis include second-generation agents with variable degrees of kinase selectivity and third-generation agents that exhibit reversible noncovalent binding to BTK. We also highlight critical considerations for the prevention and monitoring of AEs and offer practical management strategies for treatment-emergent toxicities.
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Kutsch, Nadine, Reinhard Marks, Richard Ratei, Thomas K. Held, and Martin Schmidt-Hieber. "Role of Tyrosine Kinase Inhibitors in Indolent and Other Mature B-Cell Neoplasms." Biomarker Insights 10s3 (January 2015): BMI.S22434. http://dx.doi.org/10.4137/bmi.s22434.
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Targeting tyrosine kinases represents a highly specific treatment approach for different malignancies. This also includes non-Hodgkin lymphoma since it is well known that these enzymes are frequently involved in the lymphomagenesis. Hereby, tyrosine kinases might either be dysregulated intrinsically or be activated within signal transduction pathways leading to tumor survival and growth. Among others, Bruton's tyrosine kinase (Btk) is of particular interest as a potential therapeutic target. Btk is stimulated by B-cell receptor signaling and activates different transcription factors such as nuclear factor KB. The Btk inhibitor ibrutinib has been approved for the treatment of chronic lymphocytic leukemia and mantle-cell lymphoma recently. Numerous clinical trials evaluating this agent in different combinations (eg, with rituximab or classical chemotherapeutic agents) as a treatment option for aggressive and indolent lymphoma are under way. Here, we summarize the role of tyrosine kinase inhibitors in the treatment of indolent and other non-Hodgkin lymphomas (eg, mantle-cell lymphoma).
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Yamaoka, Toshimitsu, Sojiro Kusumoto, Koichi Ando, Motoi Ohba, and Tohru Ohmori. "Receptor Tyrosine Kinase-Targeted Cancer Therapy." International Journal of Molecular Sciences 19, no. 11 (November 6, 2018): 3491. http://dx.doi.org/10.3390/ijms19113491.
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In the past two decades, several molecular targeted inhibitors have been developed and evaluated clinically to improve the survival of patients with cancer. Molecular targeted inhibitors inhibit the activities of pathogenic tyrosine kinases. Particularly, aberrant receptor tyrosine kinase (RTK) activation is a potential therapeutic target. An increased understanding of genetics, cellular biology and structural biology has led to the development of numerous important therapeutics. Pathogenic RTK mutations, deletions, translocations and amplification/over-expressions have been identified and are currently being examined for their roles in cancers. Therapies targeting RTKs are categorized as small-molecule inhibitors and monoclonal antibodies. Studies are underway to explore abnormalities in 20 types of RTK subfamilies in patients with cancer or other diseases. In this review, we describe representative RTKs important for developing cancer therapeutics and predicting or evaluated resistance mechanisms.
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Logie, Emilie, Chandra S. Chirumamilla, Claudina Perez-Novo, Priyanka Shaw, Ken Declerck, Ajay Palagani, Savithri Rangarajan, et al. "Covalent Cysteine Targeting of Bruton’s Tyrosine Kinase (BTK) Family by Withaferin-A Reduces Survival of Glucocorticoid-Resistant Multiple Myeloma MM1 Cells." Cancers 13, no. 7 (March 31, 2021): 1618. http://dx.doi.org/10.3390/cancers13071618.
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Multiple myeloma (MM) is a hematological malignancy characterized by plasma cells’ uncontrolled growth. The major barrier in treating MM is the occurrence of primary and acquired therapy resistance to anticancer drugs. Often, this therapy resistance is associated with constitutive hyperactivation of tyrosine kinase signaling. Novel covalent kinase inhibitors, such as the clinically approved BTK inhibitor ibrutinib (IBR) and the preclinical phytochemical withaferin A (WA), have, therefore, gained pharmaceutical interest. Remarkably, WA is more effective than IBR in killing BTK-overexpressing glucocorticoid (GC)-resistant MM1R cells. To further characterize the kinase inhibitor profiles of WA and IBR in GC-resistant MM cells, we applied phosphopeptidome- and transcriptome-specific tyrosine kinome profiling. In contrast to IBR, WA was found to reverse BTK overexpression in GC-resistant MM1R cells. Furthermore, WA-induced cell death involves covalent cysteine targeting of Hinge-6 domain type tyrosine kinases of the kinase cysteinome classification, including inhibition of the hyperactivated BTK. Covalent interaction between WA and BTK could further be confirmed by biotin-based affinity purification and confocal microscopy. Similarly, molecular modeling suggests WA preferably targets conserved cysteines in the Hinge-6 region of the kinase cysteinome classification, favoring inhibition of multiple B-cell receptors (BCR) family kinases. Altogether, we show that WA’s promiscuous inhibition of multiple BTK family tyrosine kinases represents a highly effective strategy to overcome GC-therapy resistance in MM.
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García-Aranda, Marilina, and Maximino Redondo. "Targeting Receptor Kinases in Colorectal Cancer." Cancers 11, no. 4 (March 27, 2019): 433. http://dx.doi.org/10.3390/cancers11040433.
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Colorectal cancer is the third most common malignancy in men and the second most common cancer in women. Despite the success of screening programs and the development of adjuvant therapies, the global burden of colorectal cancer is expected to increase by 60% to more than 2.2 million new cases and 1.1 million deaths by 2030. In recent years, a great effort has been made to demonstrate the utility of protein kinase inhibitors for cancer treatment. Considering this heterogeneous disease is defined by mutations that activate different Receptor Tyrosine Kinases (RTKs) and affect downstream components of RTK-activated transduction pathways, in this review we analyze the potential utility of different kinase inhibitors for colorectal cancer treatment.
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K. Bhanumathy, Kalpana, Amrutha Balagopal, Frederick S. Vizeacoumar, Franco J. Vizeacoumar, Andrew Freywald, and Vincenzo Giambra. "Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia." Cancers 13, no. 2 (January 7, 2021): 184. http://dx.doi.org/10.3390/cancers13020184.
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Protein kinases constitute a large group of enzymes catalysing protein phosphorylation and controlling multiple signalling events. The human protein kinase superfamily consists of 518 members and represents a complicated system with intricate internal and external interactions. Protein kinases are classified into two main families based on the ability to phosphorylate either tyrosine or serine and threonine residues. Among the 90 tyrosine kinase genes, 58 are receptor types classified into 20 groups and 32 are of the nonreceptor types distributed into 10 groups. Tyrosine kinases execute their biological functions by controlling a variety of cellular responses, such as cell division, metabolism, migration, cell–cell and cell matrix adhesion, cell survival and apoptosis. Over the last 30 years, a major focus of research has been directed towards cancer-associated tyrosine kinases owing to their critical contributions to the development and aggressiveness of human malignancies through the pathological effects on cell behaviour. Leukaemia represents a heterogeneous group of haematological malignancies, characterised by an uncontrolled proliferation of undifferentiated hematopoietic cells or leukaemia blasts, mostly derived from bone marrow. They are usually classified as chronic or acute, depending on the rates of their progression, as well as myeloid or lymphoblastic, according to the type of blood cells involved. Overall, these malignancies are relatively common amongst both children and adults. In malignant haematopoiesis, multiple tyrosine kinases of both receptor and nonreceptor types, including AXL receptor tyrosine kinase (AXL), Discoidin domain receptor 1 (DDR1), Vascular endothelial growth factor receptor (VEGFR), Fibroblast growth factor receptor (FGFR), Mesenchymal–epithelial transition factor (MET), proto-oncogene c-Src (SRC), Spleen tyrosine kinase (SYK) and pro-oncogenic Abelson tyrosine-protein kinase 1 (ABL1) mutants, are implicated in the pathogenesis and drug resistance of practically all types of leukaemia. The role of ABL1 kinase mutants and their therapeutic inhibitors have been extensively analysed in scientific literature, and therefore, in this review, we provide insights into the impact and mechanism of action of other tyrosine kinases involved in the development and progression of human leukaemia and discuss the currently available and emerging treatment options based on targeting these molecules.
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K. Bhanumathy, Kalpana, Amrutha Balagopal, Frederick S. Vizeacoumar, Franco J. Vizeacoumar, Andrew Freywald, and Vincenzo Giambra. "Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia." Cancers 13, no. 2 (January 7, 2021): 184. http://dx.doi.org/10.3390/cancers13020184.
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Protein kinases constitute a large group of enzymes catalysing protein phosphorylation and controlling multiple signalling events. The human protein kinase superfamily consists of 518 members and represents a complicated system with intricate internal and external interactions. Protein kinases are classified into two main families based on the ability to phosphorylate either tyrosine or serine and threonine residues. Among the 90 tyrosine kinase genes, 58 are receptor types classified into 20 groups and 32 are of the nonreceptor types distributed into 10 groups. Tyrosine kinases execute their biological functions by controlling a variety of cellular responses, such as cell division, metabolism, migration, cell–cell and cell matrix adhesion, cell survival and apoptosis. Over the last 30 years, a major focus of research has been directed towards cancer-associated tyrosine kinases owing to their critical contributions to the development and aggressiveness of human malignancies through the pathological effects on cell behaviour. Leukaemia represents a heterogeneous group of haematological malignancies, characterised by an uncontrolled proliferation of undifferentiated hematopoietic cells or leukaemia blasts, mostly derived from bone marrow. They are usually classified as chronic or acute, depending on the rates of their progression, as well as myeloid or lymphoblastic, according to the type of blood cells involved. Overall, these malignancies are relatively common amongst both children and adults. In malignant haematopoiesis, multiple tyrosine kinases of both receptor and nonreceptor types, including AXL receptor tyrosine kinase (AXL), Discoidin domain receptor 1 (DDR1), Vascular endothelial growth factor receptor (VEGFR), Fibroblast growth factor receptor (FGFR), Mesenchymal–epithelial transition factor (MET), proto-oncogene c-Src (SRC), Spleen tyrosine kinase (SYK) and pro-oncogenic Abelson tyrosine-protein kinase 1 (ABL1) mutants, are implicated in the pathogenesis and drug resistance of practically all types of leukaemia. The role of ABL1 kinase mutants and their therapeutic inhibitors have been extensively analysed in scientific literature, and therefore, in this review, we provide insights into the impact and mechanism of action of other tyrosine kinases involved in the development and progression of human leukaemia and discuss the currently available and emerging treatment options based on targeting these molecules.
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Staudt, Dilana, Heather Murray, Tabitha McLachlan, Frank Alvaro, Anoop Enjeti, Nicole Verrills, and Matthew Dun. "Targeting Oncogenic Signaling in Mutant FLT3 Acute Myeloid Leukemia: The Path to Least Resistance." International Journal of Molecular Sciences 19, no. 10 (October 16, 2018): 3198. http://dx.doi.org/10.3390/ijms19103198.
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The identification of recurrent driver mutations in genes encoding tyrosine kinases has resulted in the development of molecularly-targeted treatment strategies designed to improve outcomes for patients diagnosed with acute myeloid leukemia (AML). The receptor tyrosine kinase FLT3 is the most commonly mutated gene in AML, with internal tandem duplications within the juxtamembrane domain (FLT3-ITD) or missense mutations in the tyrosine kinase domain (FLT3-TKD) present in 30–35% of AML patients at diagnosis. An established driver mutation and marker of poor prognosis, the FLT3 tyrosine kinase has emerged as an attractive therapeutic target, and thus, encouraged the development of FLT3 tyrosine kinase inhibitors (TKIs). However, the therapeutic benefit of FLT3 inhibition, particularly as a monotherapy, frequently results in the development of treatment resistance and disease relapse. Commonly, FLT3 inhibitor resistance occurs by the emergence of secondary lesions in the FLT3 gene, particularly in the second tyrosine kinase domain (TKD) at residue Asp835 (D835) to form a ‘dual mutation’ (ITD-D835). Individual FLT3-ITD and FLT3-TKD mutations influence independent signaling cascades; however, little is known about which divergent signaling pathways are controlled by each of the FLT3 specific mutations, particularly in the context of patients harboring dual ITD-D835 mutations. This review provides a comprehensive analysis of the known discrete and cooperative signaling pathways deregulated by each of the FLT3 specific mutations, as well as the therapeutic approaches that hold the most promise of more durable and personalized therapeutic approaches to improve treatments of FLT3 mutant AML.
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Levis, Mark, and Alexander E. Perl. "Gilteritinib: potent targeting of FLT3 mutations in AML." Blood Advances 4, no. 6 (March 24, 2020): 1178–91. http://dx.doi.org/10.1182/bloodadvances.2019000174.
Full textAbstract:
Abstract Since the discovery of FMS-like tyrosine kinase-3 (FLT3)–activating mutations as genetic drivers in acute myeloid leukemia (AML), investigators have tried to develop tyrosine kinase inhibitors that could effectively target FLT3 and alter the disease trajectory. Giltertinib (formerly known as ASP2215) is a novel compound that entered the field late, but moved through the developmental process with remarkable speed. In many ways, this drug’s rapid development was facilitated by the large body of knowledge gained over the years from efforts to develop other FLT3 inhibitors. Single-agent gilteritinib, a potent and selective oral FLT3 inhibitor, improved the survival of patients with relapsed or refractory FLT3-mutated AML compared with standard chemotherapy. This continues to validate the approach of targeting FLT3 itself and establishes a new backbone for testing combination regimens. This review will frame the preclinical and clinical development of gilteritinib in the context of the lessons learned from its predecessors.
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Baselga, José, and Carlos L. Arteaga. "Critical Update and Emerging Trends in Epidermal Growth Factor Receptor Targeting in Cancer." Journal of Clinical Oncology 23, no. 11 (April 10, 2005): 2445–59. http://dx.doi.org/10.1200/jco.2005.11.890.
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The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase of the ErbB receptor family that is abnormally activated in many epithelial tumors. The aberrant activation of the EGFR leads to enhanced proliferation and other tumor-promoting activities, which provide a strong rationale to target this receptor family. There are two classes of anti-EGFR agents: monoclonal antibodies (MAbs) directed at the extracellular domain of the receptor and small molecule, adenosine triphosphate–competitive inhibitors of the receptor's tyrosine kinase. Anti-EGFR MAbs have shown antitumor activity in advanced colorectal carcinoma, squamous cell carcinomas of the head and neck, non–small-cell lung cancer (NSCLC) and renal cell carcinomas. The tyrosine kinase inhibitors (TKIs) have a partially different activity profile. They are active against NSCLC, and a specific EGFR inhibitor has shown improvement in survival. Recently, mutations and amplifications of the EGFR gene have been identified in NSCLC and predict for enhanced sensitivity to anti-EGFR TKIs. In addition to specific anti-EGFR TKIs, there are broader acting inhibitors such as dual EGFR HER-2 inhibitors and combined anti-pan-ErbB and antivascular endothelial growth factor receptor inhibitors. Current research efforts are directed at selecting the optimal dose and schedule and identifying predictive factors of response and resistance beyond EGFR gene mutations and/or amplifications. Finally, there is a need for improved strategies to integrate anti-EGFR agents with conventional therapies and to explore combinations with other molecular targeted approaches including other antireceptor therapies, receptor-downstream signaling transduction inhibitors, and targeted approaches interfering with other essential drivers of cancer, such as angiogenesis.
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Rendell, Aimee, Isobel Thomas-Bland, Lee McCuish, Christopher Taylor, Mudra Binju, and Yu Yu. "Targeting Tyrosine Kinases in Ovarian Cancer: Small Molecule Inhibitor and Monoclonal Antibody, Where Are We Now?" Biomedicines 10, no. 9 (August 29, 2022): 2113. http://dx.doi.org/10.3390/biomedicines10092113.
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Ovarian cancer is one of the most lethal gynaecological malignancies worldwide. Despite high success rates following first time treatment, this heterogenous disease is prone to recurrence. Oncogenic activity of receptor tyrosine kinases is believed to drive the progression of ovarian cancer. Here we provide an update on the progress of the therapeutic targeting of receptor tyrosine kinases in ovarian cancer. Broadly, drug classes that inhibit tyrosine kinase/pathways can be classified as small molecule inhibitors, monoclonal antibodies, or immunotherapeutic vaccines. Small molecule inhibitors tested in clinical trials thus far include sorafenib, sunitinib, pazopanib, tivantinib, and erlotinib. Monoclonal antibodies include bevacizumab, cetuximab, pertuzumab, trastuzumab, and seribantumab. While numerous trials have been carried out, the results of monotherapeutic agents have not been satisfactory. For combination with chemotherapy, the monoclonal antibodies appear more effective, though the efficacy is limited by low frequency of target alteration and a lack of useful predictive markers for treatment stratification. There remain critical gaps for the treatment of platinum-resistant ovarian cancers; however, platinum-sensitive tumours may benefit from the combination of tyrosine kinase targeting drugs and PARP inhibitors. Immunotherapeutics such as a peptide B-cell epitope vaccine and plasmid-based DNA vaccine have shown some efficacy both as monotherapeutic agents and in combination therapy, but require further development to validate current findings. In conclusion, the tyrosine kinases remain attractive targets for treating ovarian cancers. Future development will need to consider effective drug combination, frequency of target, and developing predictive biomarker.
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Paatero, Ilkka, Ville Veikkolainen, Matias Mäenpää, Etienne Schmelzer, Heinz-Georg Belting, Lauri J. Pelliniemi, and Klaus Elenius. "ErbB4 tyrosine kinase inhibition impairs neuromuscular development in zebrafish embryos." Molecular Biology of the Cell 30, no. 2 (January 15, 2019): 209–18. http://dx.doi.org/10.1091/mbc.e18-07-0460.
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Tyrosine kinase inhibitors are widely used in the clinic, but limited information is available about their toxicity in developing organisms. Here, we tested the effect of tyrosine kinase inhibitors targeting the ErbB receptors for their effects on developing zebrafish ( Danio rerio) embryos. Embryos treated with wide-spectrum pan-ErbB inhibitors or erbb4a-targeting antisense oligonucleotides demonstrated reduced locomotion, reduced diameter of skeletal muscle fibers, and reduced expression of muscle-specific genes, as well as reduced motoneuron length. The phenotypes in the skeletal muscle, as well as the defect in motility, were rescued both by microinjection of human ERBB4 mRNA and by transposon-mediated muscle-specific ERBB4 overexpression. The role of ErbB4 in regulating motility was further controlled by targeted mutation of the endogenous erbb4a locus in the zebrafish genome by CRISPR/Cas9. These observations demonstrate a potential for the ErbB tyrosine kinase inhibitors to induce neuromuscular toxicity in a developing organism via a mechanism involving inhibition of ErbB4 function.
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Melgar, Katelyn, Morgan M. Walker, LaQuita M. Jones, Lyndsey C. Bolanos, Kathleen Hueneman, Mark Wunderlich, Jian-Kang Jiang, et al. "Overcoming adaptive therapy resistance in AML by targeting immune response pathways." Science Translational Medicine 11, no. 508 (September 4, 2019): eaaw8828. http://dx.doi.org/10.1126/scitranslmed.aaw8828.
Full textAbstract:
Targeted inhibitors to oncogenic kinases demonstrate encouraging clinical responses early in the treatment course; however, most patients will relapse because of target-dependent mechanisms that mitigate enzyme-inhibitor binding or through target-independent mechanisms, such as alternate activation of survival and proliferation pathways, known as adaptive resistance. Here, we describe mechanisms of adaptive resistance in FMS-like receptor tyrosine kinase (FLT3)–mutant acute myeloid leukemia (AML) by examining integrative in-cell kinase and gene regulatory network responses after oncogenic signaling blockade by FLT3 inhibitors (FLT3i). We identified activation of innate immune stress response pathways after treatment of FLT3-mutant AML cells with FLT3i and showed that innate immune pathway activation via the interleukin-1 receptor–associated kinase 1 and 4 (IRAK1/4) complex contributes to adaptive resistance in FLT3-mutant AML cells. To overcome this adaptive resistance mechanism, we developed a small molecule that simultaneously inhibits FLT3 and IRAK1/4 kinases. The multikinase FLT3-IRAK1/4 inhibitor eliminated adaptively resistant FLT3-mutant AML cells in vitro and in vivo and displayed superior efficacy as compared to current targeted FLT3 therapies. These findings uncover a polypharmacologic strategy for overcoming adaptive resistance to therapy in AML by targeting immune stress response pathways.
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Ota, Yoko, Hiroyuki Yoda, Takahiro Inoue, Takayoshi Watanabe, Yoshinao Shinozaki, Atsushi Takatori, and Hiroki Nagase. "Targeting anaplastic lymphoma kinase (ALK) gene alterations in neuroblastoma by using alkylating pyrrole-imidazole polyamides." PLOS ONE 16, no. 9 (September 30, 2021): e0257718. http://dx.doi.org/10.1371/journal.pone.0257718.
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Anaplastic lymphoma kinase (ALK) aberration is related to high-risk neuroblastomas and is an important therapeutic target. As acquired resistance to ALK tyrosine kinase inhibitors is inevitable, novel anti-ALK drug development is necessary in order to overcome potential drug resistance against ATP-competitive kinase inhibitors. In this study, to overcome ALK inhibitor resistance, we examined the growth inhibition effects of newly developed ALK-targeting pyrrole-imidazole polyamide CCC-003, which was designed to directly bind and alkylate DNA within the F1174L-mutated ALK gene. CCC-003 suppressed cell proliferation in ALK-mutated neuroblastoma cells. The expression of total and phosphorylated ALK was downregulated by CCC-003 treatment but not by treatment with a mismatch polyamide without any binding motif within the ALK gene region. CCC-003 preferentially bound to the DNA sequence with the F1174L mutation and significantly suppressed tumor progression in a human neuroblastoma xenograft mouse model. Our data suggest that the specific binding of CCC-003 to mutated DNA within the ALK gene exerts its anti-tumor activity through a mode of action that is distinct from those of other ALK inhibitors. In summary, our current study provides evidence for the potential of pyrrole-imidazole polyamide ALK inhibitor CCC-003 for the treatment of neuroblastoma thus offering a possible solution to the problem of tyrosine kinase inhibitor resistance.
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Moradpour, Zahra, and Leila Barghi. "Novel Approaches for Efficient Delivery of Tyrosine Kinase Inhibitors." Journal of Pharmacy & Pharmaceutical Sciences 22 (January 13, 2019): 37–48. http://dx.doi.org/10.18433/jpps29891.
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Epidermal growth factor receptors (EGFRs) have potential to be considered as therapeutic target for cancer treatment especially in cancer patients with overexpression of EGFR. Cetuximab as a first monoclonal antibody and Imatinib as the first small molecule tyrosine kinase inhibitor (SMTKI) were approved by FDA in 1998 and 2001. About 28 SMTKIs have been approved until 2015 and a large number of compound with kinase inhibitory activity are at the different phases of clinical trials. Although Kinase inhibitors target specific intracellular pathways, their tissue or cellular distribution are not specific. So treatment with these drugs causes serious dose dependent side effects. Targeted delivery of kinase inhibitors via dendrimers, polymeric nanoparticles, magnetic nanoparticles and lipid based delivery systems such as liposomes, solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) can lead to reduction of side effects and improving therapeutic efficacy of the drugs in the target organs. Furthermore formulation of these drugs is challenged by their physicochemical properties such as solubility and dissolution rate. The main approaches in order to increase dissolution rate, are particle size reduction, self-emulsification, cyclodextrin complexation, crystal modification and amorphous solid dispersion. Synergistic therapeutic effect, decreased side effects and drug resistant, reduced cost and increased patient compliance are the advantages associated with using combination therapy especially in the treatment of cancer. Combination of TKIs with chemotherapeutic agents or biopharmaceuticals such as monoclonal antibodies and oligonucleotides and also combination of two TKIs within one formulation is possible by new targeting delivery systems. This article reviews the recent advances in the design and development of delivery systems for TKIs.
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Sos, Martin L., Hannah Lea Tumbrink, Carsten Schultz-Fademrecht, Jonas Lategahn, Marina Keul, Janina Niggenaber, Alena Heimsoeth, et al. "Targeting EGFR Ex20 mutant lung cancer with the wild type sparing kinase inhibitor PRB001." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e14718-e14718. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14718.
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e14718 Background: The majority of EGFR mutant tumors can be effectively treated with targeted drugs. Lung adenocarcinoma patients with EGFR Ex20 insertion mutations, however, lack safe and potent treatment options. These genetic alterations share homology with HER2 Ex20 insertion mutations and perturb the ATP binding pocket in a way that limits accessibility through currently available tyrosine kinase inhibitors. Second-generation EGFR inhibitors are partially active in EGFR Ex20 mutant models but their potent activity against wild type (WT) EGFR and the resulting adverse effects largely prohibit the clinical use of these drugs. To address this medical need, we developed PRB001, a novel EGFR kinase inhibitor. Methods: We facilitated protein X-ray crystallography to guide the development of small molecule inhibitors with high potency against EGFR/HER2 Ex20 mutant kinases and low activity against WT EGFR. Iterative compound optimization involved biochemical profiling concerning inhibition and binding kinetics, cellular profiling as well as mouse pharmacokinetic and mouse efficacy studies. Results: PRB001 exhibits potent activity against EGFR/HER2 Ex20 insertion mutations, in genetically engineered Ba/F3 cell line models and patient derived cell lines. At the same time, PRB001 exhibits a 10-100 fold lower activity against WT EGFR in several cellular models. Our data indicate that PRB001 and its derivatives display a therapeutic window for an effective treatment of EGFR Ex20 mutant tumors with a limited toxicity profile. Mouse xenograft experiments support these results, showing that, in contrast to second-generation EGFR inhibitors, PRB001 does not inhibit WT EGFR and does not lead to loss of weight of treated animals at effective doses of 90 mg/kg daily. Conclusions: Our data support the notion that PRB001 effectively kills a wide range of EGFR Ex20 mutant cellular models and together with its safety profile builds a basis for the development of a mutant-selective and clinically effective tyrosine kinase inhibitor.
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Chase, Andrew, and Nicholas C. P. Cross. "Signal transduction therapy in haematological malignancies: identification and targeting of tyrosine kinases." Clinical Science 111, no. 4 (September 13, 2006): 233–49. http://dx.doi.org/10.1042/cs20060035.
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Tyrosine kinases play key roles in cell proliferation, survival and differentiation. Their aberrant activation, caused either by the formation of fusion genes by chromosome translocation or by intragenic changes, such as point mutations or internal duplications, is of major importance in the development of many haematological malignancies. An understanding of the mechanisms by which BCR-ABL contributes to the pathogenesis of chronic myeloid leukaemia led to the development of imatinib, the first of several tyrosine kinase inhibitors to enter clinical trials. Although the development of resistance has been problematic, particularly in aggressive disease, the development of novel inhibitors and combination with other forms of therapy shows promise.
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Chew, Serena, Melissa C. Mackey, and Elias Jabbour. "Gilteritinib in the treatment of relapsed and refractory acute myeloid leukemia with a FLT3 mutation." Therapeutic Advances in Hematology 11 (January 2020): 204062072093061. http://dx.doi.org/10.1177/2040620720930614.
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Acute myeloid leukemia (AML) is a malignancy of uncontrolled proliferation of immature myeloid blasts characterized by clonal evolution and genetic heterogeneity. FMS-like tyrosine kinase 3 (FLT3) mutations occur in up to a third of AML cases and are associated with highly proliferative disease, shorter duration of remission, and increased rates of disease relapse. The known impact of activating mutations in FLT3 in AML on disease pathogenesis, prognosis, and response to therapy has led to the development of tyrosine kinase inhibitors targeting FLT3. Gilteritinib is a potent, second generation inhibitor of both FLT3 and AXL, designed to address the limitations of other FLT3 inhibitors, particularly in targeting mechanisms of resistance to other drugs. In this review, we present comprehensive data on recent and ongoing studies evaluating the role of gilteritinib in the relapsed and refractory FLT3 mutated AML setting.
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Amelia, Tasia, Rahmana Emran Kartasasmita, Tomohiko Ohwada, and Daryono Hadi Tjahjono. "Structural Insight and Development of EGFR Tyrosine Kinase Inhibitors." Molecules 27, no. 3 (January 26, 2022): 819. http://dx.doi.org/10.3390/molecules27030819.
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Lung cancer has a high prevalence, with a growing number of new cases and mortality every year. Furthermore, the survival rate of patients with non-small-cell lung carcinoma (NSCLC) is still quite low in the majority of cases. Despite the use of conventional therapy such as tyrosine kinase inhibitor for Epidermal Growth Factor Receptor (EGFR), which is highly expressed in most NSCLC cases, there was still no substantial improvement in patient survival. This is due to the drug’s ineffectiveness and high rate of resistance among individuals with mutant EGFR. Therefore, the development of new inhibitors is urgently needed. Understanding the EGFR structure, including its kinase domain and other parts of the protein, and its activation mechanism can accelerate the discovery of novel compounds targeting this protein. This study described the structure of the extracellular, transmembrane, and intracellular domains of EGFR. This was carried out along with identifying the binding pose of commercially available inhibitors in the ATP-binding and allosteric sites, thereby clarifying the research gaps that can be filled. The binding mechanism of inhibitors that have been used clinically was also explained, thereby aiding the structure-based development of new drugs.
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Aubry, Arthur, Stéphane Galiacy, and Michèle Allouche. "Targeting ALK in Cancer: Therapeutic Potential of Proapoptotic Peptides." Cancers 11, no. 3 (February 26, 2019): 275. http://dx.doi.org/10.3390/cancers11030275.
Full textAbstract:
ALK is a receptor tyrosine kinase, associated with many tumor types as diverse as anaplastic large cell lymphomas, inflammatory myofibroblastic tumors, breast and renal cell carcinomas, non-small cell lung cancer, neuroblastomas, and more. This makes ALK an attractive target for cancer therapy. Since ALK–driven tumors are dependent for their proliferation on the constitutively activated ALK kinase, a number of tyrosine kinase inhibitors have been developed to block tumor growth. While some inhibitors are under investigation in clinical trials, others are now approved for treatment, notably in ALK-positive lung cancer. Their efficacy is remarkable, however limited in time, as the tumors escape and become resistant to the treatment through different mechanisms. Hence, there is a pressing need to target ALK-dependent tumors by other therapeutic strategies, and possibly use them in combination with kinase inhibitors. In this review we will focus on the therapeutic potential of proapoptotic ALK-derived peptides based on the dependence receptor properties of ALK. We will also try to make a non-exhaustive list of several alternative treatments targeting ALK-dependent and independent signaling pathways.
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Hsu, Jonathan, Jun Zhang, Chris Kitson, Seng-Lai Tan, Satwant Narula, Julie A. DeMartino, and Cheng Liao. "Development of a Pharmacodynamic Assay Based on PLCγ2 Phosphorylation for Quantifying Spleen Tyrosine Kinase (SYK)–Bruton’s Tyrosine Kinase (BTK) Signaling." Journal of Biomolecular Screening 18, no. 8 (May 23, 2013): 890–98. http://dx.doi.org/10.1177/1087057113489881.
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Spleen tyrosine kinase (SYK) and Bruton’s tyrosine kinase (BTK) are key mediators in coupling cell surface receptors, such as the B-cell receptor (BCR), to downstream signaling events affecting diverse biological functions. There is therefore tremendous interest in the development of pharmacological inhibitors targeting the SYK-BTK axis for the treatment of inflammatory disorders and hematological malignancies. A good pharmacodynamic (PD) assay, ideally a blood-based assay that measures proximal events, is warranted for evaluation of such inhibitors. In platelets, collagen-induced activation of membrane glycoprotein GPVI is dependent on the SYK-BTK axis. Here, we report the development of a novel immunoassay that uses the dissociation-enhanced lanthanide fluorescent immunoassay (DELFIA) to measure GPVI-mediated phosphorylation of phospholipase C γ2 (PLCγ2), a direct substrate of SYK and BTK, in platelets. The assay was validated using SYK or BTK inhibitors and generated IC50 correlated with those from the BCR-induced B-cell activation assay. Furthermore, this assay showed good stability and uniformity over a period of 24 h in different donors. Interestingly, compound IC50 values using blood from patients with rheumatoid arthritis were slightly higher compared with those produced using samples from healthy donors. This novel platelet PLCγ2 phosphorylation-based immunoassay should serve as a promising PD assay for preclinical and clinical development of inhibitors targeting the SYK-BTK axis.
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Alcalá, Sonia, Víctor Mayoral-Varo, Laura Ruiz-Cañas, Juan Carlos López-Gil, Christopher Heeschen, Jorge Martín-Pérez, and Bruno Sainz. "Targeting SRC Kinase Signaling in Pancreatic Cancer Stem Cells." International Journal of Molecular Sciences 21, no. 20 (October 9, 2020): 7437. http://dx.doi.org/10.3390/ijms21207437.
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The proto-oncogene nonreceptor tyrosine-protein kinase SRC is a member of the SRC family of tyrosine kinases (SFKs), and its activation and overexpression have been shown to play a protumorigenic role in multiple solid cancers, including pancreatic ductal adenocarcinoma (PDAC). PDAC is currently the seventh-leading cause of cancer-related death worldwide, and, by 2030, it is predicted to become the second-leading cause of cancer-related death in the United States. PDAC is characterized by its high lethality (5-year survival of rate of <10%), invasiveness, and chemoresistance, all of which have been shown to be due to the presence of pancreatic cancer stem cells (PaCSCs) within the tumor. Due to the demonstrated overexpression of SRC in PDAC, we set out to determine if SRC kinases are important for PaCSC biology using pharmacological inhibitors of SRC kinases (dasatinib or PP2). Treatment of primary PDAC cultures established from patient-derived xenografts with dasatinib or PP2 reduced the clonogenic, self-renewal, and tumor-initiating capacity of PaCSCs, which we attribute to the downregulation of key signaling factors such as p-FAK, p-ERK1-2, and p-AKT. Therefore, this study not only validates that SRC kinases are relevant and biologically important for PaCSCs but also suggests that inhibitors of SRC kinases may represent a possible future treatment option for PDAC patients, although further studies are still needed.
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Nelson, Erik A., Sarah R. Walker, Ellen Weisberg, Michal Bar-Natan, Rosemary Barrett, Laurie B. Gashin, Shariya Terrell, et al. "The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors." Blood 117, no. 12 (March 24, 2011): 3421–29. http://dx.doi.org/10.1182/blood-2009-11-255232.
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Abstract The transcription factor STAT5 is an essential mediator of the pathogenesis of chronic myelogenous leukemia (CML). In CML, the BCR/ABL fusion kinase causes the constitutive activation of STAT5, thereby driving the expression of genes promoting survival. BCR/ABL kinase inhibitors have become the mainstay of therapy for CML, although CML cells can develop resistance through mutations in BCR/ABL. To overcome this problem, we used a cell-based screen to identify drugs that inhibit STAT-dependent gene expression. Using this approach, we identified the psychotropic drug pimozide as a STAT5 inhibitor. Pimozide decreases STAT5 tyrosine phosphorylation, although it does not inhibit BCR/ABL or other tyrosine kinases. Furthermore, pimozide decreases the expression of STAT5 target genes and induces cell cycle arrest and apoptosis in CML cell lines. Pimozide also selectively inhibits colony formation of CD34+ bone marrow cells from CML patients. Importantly, pimozide induces similar effects in the presence of the T315I BCR/ABL mutation that renders the kinase resistant to presently available inhibitors. Simultaneously inhibiting STAT5 with pimozide and the kinase inhibitors imatinib or nilotinib shows enhanced effects in inhibiting STAT5 phosphorylation and in inducing apoptosis. Thus, targeting STAT5 may be an effective strategy for the treatment of CML and other myeloproliferative diseases.
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Chen, Yun, Yao Guo, Wanting Ho, and Zhizhuang Joe. "Identification and Characterization Of a Potent FLT3 Inhibitor." Blood 122, no. 21 (November 15, 2013): 5027. http://dx.doi.org/10.1182/blood.v122.21.5027.5027.
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Abstract Acute myeloid leukemia (AML) is a malignant myeloid disorder for which there is no effective treatment. Gain-of-function mutations of tyrosine kinase FLT3 are frequently found in AML patients. This makes FLT3 an attractive therapeutic target. Currently, several potent FLT3 inhibitors have been developed. However, their clinical efficacy is limited largely due to their poor effectiveness toward the FLT3-D835 mutants which are often present in AML or acquired after treatment of FLT3-ITD-positive AML with tyrosine kinase inhibitors. Needless to say, more potent FLT3 inhibitors targeting both FLT-ITD and FLT3-D835 mutants are needed. In addition, combinations of tyrosine kinase inhibitors with drugs targeting other signaling pathways represent a new trend in anti-cancer drug development. To establish an effective kinase assay for FLT3 inhibitor screening, we generated a protein substrate designated GST-FLT3S which was expressed in E. coli cells as a glutathione S-transferase fusion protein. The protein substrate together with recombinant proteins containing the catalytic domain of wild type and mutant forms of FLT3 expressed in baculovirus was used in biochemical screening of inhibitors. Several potent inhibitors were obtained. Importantly, one of the inhibitors with an oxindole core structure inhibited FLT3 and D835 FLT3 mutants equally well with nanomolar IC50 values. We further analyzed the potency of the inhibitor by performing cell-based assays. The cells used included FLT3-ITD-positive cell line MV-4-11 and an EPO-dependent erythroleukemia cell line transformed by retrovirus mediated expressions of FLT3-ITD and FLT3-D835 mutants. At nanomolar concentrations, the inhibitor blocked growth factor signaling and effectively caused apoptosis and cell cycle arrest. It showed significant advantage over the current available FLT3 inhibitor, sorafenib. Loss-of-function mutations of tumor suppressor p53 are common in solid tumors but relatively rare in AML although its expression is often suppressed. This makes p53 a potential target for anti-AML drug development. We employed MDM2 inhibitor nutlin-3 which blocks the degradation of p53. Importantly, at sub-nanomolar concentrations, FLT3 inhibitors and nutlin-3 synergistically inhibited growth of cells containing FLT3-ITD or FLT3-D835 mutants. Altogether, we developed an effective substrate for screening of FLT3 inhibitors and identified one compound with high potency toward both FLT3-ITD and FLT3-D835. We further demonstrated that targeting FLT3 and p53 simultaneously greatly increases drug potency. Disclosures: No relevant conflicts of interest to declare.
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Capparelli, Claudia, Timothy Purwin, and Andrew Aplin. "Abstract B05: Sox10 differentially regulates receptor tyrosine kinase expression in melanomas." Cancer Research 80, no. 19_Supplement (October 1, 2020): B05. http://dx.doi.org/10.1158/1538-7445.mel2019-b05.
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Abstract Targeting the ErbB3-ErbB2 pathway increases the efficacy of MEK inhibitors in melanoma. Given the inter- and intratumor heterogeneity of melanoma, identifying biomarkers for cells within tumors that will respond effectively to MEK inhibitor-anti-ErbB3 cotargeting is crucial. To this end, we sought to identify transcriptional regulators of ErbB3. Several transcription factors (TFs) are predicted to bind to the promoter region of ErbB3. Using correlation analysis, SOX10 was positively correlated with ErbB3 expression in the RNA-seq data from TCGA cutaneous melanoma dataset. By contrast, an inverse correlation existed between SOX10 and other receptor tyrosine kinases, EGFR and PDGFR, which have been associated with a slow-growing phenotype and resistance to BRAF and MEK inhibitors. siRNA and CRISPR knockdown/out experiments confirmed that SOX10 positively regulates ErbB3 but negatively regulates PDGFR, suggesting plasticity between SOX10-positive and SOX10-negative populations with regard to RTK expression. Overall, this study suggests that SOX10 is a potential biomarker of responsiveness to MEK inhibitor plus ErbB3 targeting antibody in melanoma. Citation Format: Claudia Capparelli, Timothy Purwin, Andrew Aplin. Sox10 differentially regulates receptor tyrosine kinase expression in melanomas [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B05.
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Thomas, Christan M., and Peter Campbell. "FLT3 inhibitors in acute myeloid leukemia: Current and future." Journal of Oncology Pharmacy Practice 25, no. 1 (September 30, 2018): 163–71. http://dx.doi.org/10.1177/1078155218802620.
Full textAbstract:
FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase that is responsible for the proliferation and survival of hematopoietic stem cells in acute myeloid leukemia. Although patients with FLT3 mutations have similar rates of remission following induction chemotherapy, relapse rates are significantly higher and patients with FLT3 mutations have significantly worse outcomes for overall survival and disease-free survival. Early FLT3 inhibitors, such as sorafenib, were non-selective and inhibited several tyrosine kinase receptors resulting in significant toxicity. The treatment of FLT3-positive acute myeloid leukemia has advanced recently with the development of a several FLT3-targeting agents that are either approved or in development. Midostaurin represents the first FDA-approved treatment targeted against FLT3, and there are several promising agents currently undergoing clinical trials. Although certain mutations confer resistance to earlier generation FLT3-targeted tyrosine kinase inhibitors, newer agents show activity in the presence of these mutations.
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Cho, Hyewon, Eun Lee, Hye Ah Kwon, Lee Seul, Hui-Jeon Jeon, Ji Hoon Yu, Jae-Ha Ryu, and Raok Jeon. "Discovery of Tricyclic Pyranochromenone as Novel Bruton’s Tyrosine Kinase Inhibitors with In Vivo Antirheumatic Activity." International Journal of Molecular Sciences 21, no. 21 (October 25, 2020): 7919. http://dx.doi.org/10.3390/ijms21217919.
Full textAbstract:
Bruton’s tyrosine kinase (BTK) is an attractive target for treating patients with B cell malignancies and autoimmune diseases. Many BTK inhibitors have been identified; however, like other kinase inhibitors, they lack diversity in their core structures. Therefore, it is important to secure a novel scaffold that occupies the adenine-binding site of BTK. We screened an in-house library of natural products and their analogs via a biochemical assay to identify a novel scaffold for targeting BTK. A pyranochromenone scaffold, derived from a natural active component decursin, was found to be effective at targeting BTK and was selected for further optimization. A series of pyranochromenone analogs was synthesized through the modification of pyranochromenone at the C7 position. Pyranochromenone compounds with an electrophilic warhead exhibited promising BTK inhibitory activity, with IC50 values in the range of 0.5–0.9 µM. A docking study of the representative compound 8 provided a reasonable explanation for compound activity. Compound 8 demonstrated good selectivity over other associated kinases and decreased the production of proinflammatory cytokines in THP cells. Moreover, compound 8 presented significant in vivo efficacy in a murine model of collagen-induced arthritis.
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Tyner, Jeffrey W., Stephanie Willis, Michael W. N. Deininger, and Brian J. Druker. "RNAi Functional Screening of the Tyrosine Kinome Identifies Therapeutic Targets in Acute Myeloid Leukemia Patients." Blood 110, no. 11 (November 16, 2007): 208. http://dx.doi.org/10.1182/blood.v110.11.208.208.
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Abstract A large percentage of cancer cases present without knowledge of the causative genetic events. Tyrosine kinases are frequently implicated in the pathogenesis of cancer, but identification of specific tyrosine kinases as cancer targets has been a slow process. Tyrosine kinases are thought to play a causative role in acute myeloid leukemia (AML), based in part on the high percentage of cases with phosphorylation of STAT5—a marker for activity of tyrosine kinase signaling. However, known abnormalities in tyrosine kinases in AML are restricted to internal tandem duplications of FLT3 or genetic aberrations in FLT3, c-KIT, and a few other genes. Thus, the specific tyrosine kinases that form the basis for targeted intervention have remained unclear in the majority of AML patients. Here, we report a novel assay by which cells from AML patients are functionally screened with RNAi to elucidate tyrosine kinase targets amenable to therapeutic intervention. Methods: To determine targets necessary for viability of malignant cells, we screened cell lines as well as primary cells from AML patients by electroporating siRNAs individually targeting each member of the tyrosine kinase family. Four days later, we determined the cell viability and tabulated sensitivity of the cells to any individual tyrosine kinase. Where possible, results were confirmed by treating samples with small-molecule inhibitors with activity against the genes identified by the assay. In addition, the mechanism of oncogenesis was investigated for each positive result. Results: We demonstrate that siRNA screening can identify tyrosine kinase targets containing activating mutations in JAK3 (A572V) in CMK cells (Figure 1) and c-KIT (V560G) in HMC1.1 cells. In addition, this assay identifies targets that do not contain mutations, such as JAK1 (Figure 1) and the focal adhesion kinases, yet are still crucial to the survival of the cells. We have also used this assay to determine sensitivity of numerous primary AML samples to inhibition of individual tyrosine kinases. Candidate targets found in primary samples include FLT1, PDGFR, JAK1/3, JAK2, CSF1R, ROR1, and EPHA5. Studies using small-molecule kinase inhibitors have confirmed sensitivity of specific samples to inhibition of target genes identified by the assay. Finally, the mechanism of oncogenesis and its relation to the gene target has been established in select samples with genetic abnormalities ranging from point mutations and insertional mutations to evidence of chromosomal rearrangements. Conclusions: We demonstrate that RNAi functional screening can determine sensitivity to individual tyrosine kinases, both in cell lines and in primary samples. For the first time, this technique offers the potential to match specific therapies for targeted intervention with individual patients based on a functional assay. Figure 1. CMK cells were transfected with an siRNA library individually targeting each member of the tyrosine kinase family, N-RAS, K-RAS, and non-specific controls. Cell viability was determined by an MTS assay 4 days later. Each bar represents an individual kinase with values shown as percent mean ± s.e.m (n = 3) (normalized to non-specific controls). Figure 1. CMK cells were transfected with an siRNA library individually targeting each member of the tyrosine kinase family, N-RAS, K-RAS, and non-specific controls. Cell viability was determined by an MTS assay 4 days later. Each bar represents an individual kinase with values shown as percent mean ± s.e.m (n = 3) (normalized to non-specific controls).
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Olsen, Colin E., Eric S. Gourley, Xiao-Hui Lui, Jeff Walker, Cory L. Grand, Steven L. Warner, Hariprasad Vankayalapati, and David J. Bearss. "Targeting the JAK2 Kinase in Hematological Malignancies." Blood 110, no. 11 (November 16, 2007): 3560. http://dx.doi.org/10.1182/blood.v110.11.3560.3560.
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Abstract JAK2 is an intracellular protein tyrosine kinase whose dysregulation has been implicated in leukemia, lymphoma, and myeloproliferative disorders (MPD). Increased kinase activity of JAK2, caused by point mutation of the JH2 autoinhibitory region or formation of JAK2 fusion proteins, causes increased activation of downstream signaling pathways affecting cell differentiation, proliferation, migration, and apoptosis. Through the use of CLIMB™, our proprietary drug discovery process, the published JAK2 crystal structure was used to build several models that were then used as a substrate for in silico docking of 2.3 million virtual small molecule compounds to generate a subset of leads based on calculated binding energies. These leads were further screened using a number of in silico physicochemical and ADMET prediction algorithms to determine “druggable” leads which were most likely to be successful in a biological context. Lead JAK2 inhibitor candidates exhibit low nanomolar IC50 activity against the JAK2 and JAK2 V617F mutant enzymes. Cancer cell lines expressing either the wild-type or mutant JAK2 enzyme demonstrate sensitivity to these inhibitors resulting in IC50 values in low micromolar to nanomolar range. Consistent with the inhibition of the JAK2 enzyme, activity of downstream signaling partners are severely decreased. The phosphorylation level of STAT5, a downstream modulator of JAK2 signaling, in treated HEL cell lysates was analyzed by western blot analysis. These results showed that lead JAK2 candidates caused an inhibition of STAT5 phosphorylation at a low nanomolar EC50. This series of compounds are currently being tested in in vivo xenograft models. Evaluation of lead candidates in biochemical assays against the hERG and CYP450 enzymes showed that these compounds have little inhibitory activity against these enzymes. SuperGen’s lead selective JAK2 inhibitors exhibit potent inhibition of wild-type and mutant JAK2 kinase activity translating into potent inhibition of cellular signaling pathways and cancer cell proliferation.
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Padi, Sathish Kumar Reddy, Libia A. Luevano, Ningfei An, Ritu Pandey, Neha Singh, Jin H. Song, Jon C. Aster, Xue-Zhong Yu, Shikhar Mehrotra, and Andrew S. Kraft. "Therapeutic Targeting of PIM Protein Kinases in a Subset of T-Cell Acute Lymphoblastic Leukemia." Blood 128, no. 22 (December 2, 2016): 2742. http://dx.doi.org/10.1182/blood.v128.22.2742.2742.
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Abstract New approaches are needed to treat and cure T-cell acute lymphoblastic leukemia (T-ALL) patients who are currently failing to achieve a remission with chemotherapy. While very intensive chemotherapy regimens result in remission in many T-ALL patients, early T-cell precursor (ETP)-ALL, defined by the absence of CD4, CD8, and CD1a and frequent expression of one or more myeloid markers, is associated with a higher rate of relapse and induction failure with a 10-year overall survival of 19% as compared with 84% for all other T-ALLs. The PIM serine/threonine protein kinase has been identified as a potential novel target for the development of new treatment regimens for the cure of hematopoietic malignancies. To explore the potential association of elevated PIM1 expression with ETP-ALL, we analyzed a publically available St. Judes gene expression dataset GSE28703. Results demonstrated that PIM1 is highly expressed in 75% of patients with ETP-ALL and in 13% of non-ETP ALL. PIM1 overexpression in immature or ETP-ALL is further validated using two other publically available independent cohorts: E-MEXP-313 and GSE62156. Based on this observation, we then tested the ability of pan-PIM inhibitors (AZD1208/LGB-321) on the growth of 6 human T-ALL cell lines. qRT-PCR and western blot analysis confirmed, PIM inhibitor sensitive (XTT assay: IC50 < 1 micromolar) cell lines (H-SB2, DU.528, and KOPT-K1) had elevated levels of PIM1 (>9 folds, p<0.01), activated JAK/STAT pathway and lower levels of MYC. Sensitive cells (H-SB2 and DU.528), had an immature or ETP-ALL phenotype (CD4-/CD8- and TdT-). Insensitive CUTLL1, SUP-T1, and HPB-ALL (XTT assay: IC50 > 10 micromolar) cell lines express significantly low PIM1, activated NOTCH mutations, activated AKT signaling, and higher levels of MYC. Immunophenotype of all the PIM inhibitor insensitive cells lines was consistent with a more mature T-ALL phenotype (CD4+/CD8+ and TdT+). When we selected NOTCH-mutant mature T-ALL cells for resistance to gamma secretase inhibitors (SUP-T1-Persister cells) they developed elevated PIM1 kinase levels and were sensitive to the growth inhibitory activities of PIM inhibition. Thus, PIM appears to be a potential target for chemotherapeutic treatment intervention in T-ALL and especially ETP-ALL tumor cells. While PIM kinase inhibitors block ETP-ALL growth they do not induce cell death. The observation that treatment with PIM inhibitors activated ERK and STAT phosphorylation, along with the knowledge that T-ALL cells have increased levels of SRC family tyrosine kinases suggested that adding a broadly active tyrosine kinase inhibitor could enhance the killing of these tumor cells. We have made the novel observation that the combination of Ponatinib, a tyrosine kinase inhibitor used in the treatment of chronic myelogenous leukemia, with a PIM kinase inhibitor is synergistically lethal to ETP-ALL cells (CI < 1.0). These agents synergize to induce PARP and Caspase cleavage, sufficient to drive apoptosis. In murine models, following engraftment of NOD/scid/IL-2Rɣ null (NSG) mice with H-SB2-luc cell xenografts, three weeks of dual therapy with AZD1208 (30mg/kg/day) and Ponatinib (3mg/kg/day) significantly blocked leukemia growth as evidenced by optical scanning for luciferase producing cells (Figure 1, p<0.05), and reduced the number of leukemic cells (hCD45 staining) in the peripheral blood and bone marrow. This dual therapy significantly prolonged the survival (p<0.005) of the treated mice. This outcome was obtained at one-tenth of normal dose of Ponatinib used in animals, suggesting that in the humans the side effects induced by this agent could be avoided by using this combination therapy. Taken together, these findings highlight the important role for PIM protein kinase activity in T-ALL and especially in the ETP-ALL, phenotype. Tumor xenograft experiments provide strong preclinical rationale for a novel treatment strategy of combining PIM and tyrosine kinase inhibitors for treatment of patients with PIM overexpressing T-ALL. Figure 1 Combination treatment of AZD1208 and Ponatinib in H-SB2-luc xenograft model, significantly suppressed leukemia burden as compared with vehicle-treated group. Figure 1. Combination treatment of AZD1208 and Ponatinib in H-SB2-luc xenograft model, significantly suppressed leukemia burden as compared with vehicle-treated group. Disclosures No relevant conflicts of interest to declare.
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Manouchehri, Ali, Elishama Kanu, Michael J. Mauro, Aaron W. Aday, Jonathan R. Lindner, and Javid Moslehi. "Tyrosine Kinase Inhibitors in Leukemia and Cardiovascular Events." Arteriosclerosis, Thrombosis, and Vascular Biology 40, no. 2 (February 2020): 301–8. http://dx.doi.org/10.1161/atvbaha.119.313353.
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Targeted oncology therapies have revolutionized cancer treatment over the last decade and have resulted in improved prognosis for many patients. This advance has emanated from elucidation of pathways responsible for tumorigenesis followed by targeting of these pathways by specific molecules. Cardiovascular care has become an increasingly critical aspect of patient care in part because patients live longer, but also due to potential associated toxicities from these therapies. Because of the targeted nature of cancer therapies, cardiac and vascular side effects may additionally provide insights into the basic biology of vascular disease. We herein provide the example of tyrosine kinase inhibitors utilized in chronic myelogenous leukemia to illustrate this medical transformation. We describe the vascular considerations for the clinical care of chronic myelogenous leukemia patients as well as the emerging literature on mechanisms of toxicities of the individual tyrosine kinase inhibitors. We additionally postulate that basic insights into toxicities of novel cancer therapies may serve as a new platform for investigation in vascular biology and a new translational research opportunity in vascular medicine.
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Zheng, Tony J., Elizabeth R. Lofurno, Alexander R. Melrose, Hari Hara Sudhan Lakshmanan, Jiaqing Pang, Kevin G. Phillips, Meghan E. Fallon, et al. "Assessment of the effects of Syk and BTK inhibitors on GPVI-mediated platelet signaling and function." American Journal of Physiology-Cell Physiology 320, no. 5 (May 1, 2021): C902—C915. http://dx.doi.org/10.1152/ajpcell.00296.2020.
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Spleen tyrosine kinase (Syk) and Bruton’s tyrosine kinase (BTK) play critical roles in platelet physiology, facilitating intracellular immunoreceptor tyrosine-based activation motif (ITAM)-mediated signaling downstream of platelet glycoprotein VI (GPVI) and GPIIb/IIIa receptors. Small molecule tyrosine kinase inhibitors (TKIs) targeting Syk and BTK have been developed as antineoplastic and anti-inflammatory therapeutics and have also gained interest as antiplatelet agents. Here, we investigate the effects of 12 different Syk and BTK inhibitors on GPVI-mediated platelet signaling and function. These inhibitors include four Syk inhibitors, Bay 61-3606, R406 (fostamatinib), entospletinib, TAK-659; four irreversible BTK inhibitors, ibrutinib, acalabrutinib, ONO-4059 (tirabrutinib), AVL-292 (spebrutinib); and four reversible BTK inhibitors, CG-806, BMS-935177, BMS-986195, and fenebrutinib. In vitro, TKIs targeting Syk or BTK reduced platelet adhesion to collagen, dense granule secretion, and alpha granule secretion in response to the GPVI agonist cross-linked collagen-related peptide (CRP-XL). Similarly, these TKIs reduced the percentage of activated integrin αIIbβ3 on the platelet surface in response to CRP-XL, as determined by PAC-1 binding. Although all TKIs tested inhibited phospholipase C γ2 (PLCγ2) phosphorylation following GPVI-mediated activation, other downstream signaling events proximal to phosphoinositide 3-kinase (PI3K) and PKC were differentially affected. In addition, reversible BTK inhibitors had less pronounced effects on GPIIb/IIIa-mediated platelet spreading on fibrinogen and differentially altered the organization of PI3K around microtubules during platelets spreading on fibrinogen. Select TKIs also inhibited platelet aggregate formation on collagen under physiological flow conditions. Together, our results suggest that TKIs targeting Syk or BTK inhibit central platelet functional responses but may differentially affect protein activities and organization in critical systems downstream of Syk and BTK in platelets.
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Nordigården, Amanda, Maria Kraft, Pernilla Eliasson, Verena Labi, Eric W. F. Lam, Andreas Villunger, and Jan-Ingvar Jönsson. "BH3-only protein Bim more critical than Puma in tyrosine kinase inhibitor–induced apoptosis of human leukemic cells and transduced hematopoietic progenitors carrying oncogenic FLT3." Blood 113, no. 10 (March 5, 2009): 2302–11. http://dx.doi.org/10.1182/blood-2008-07-167023.
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Abstract Constitutively activating internal tandem duplications (ITD) of FLT3 (FMS-like tyrosine kinase 3) are the most common mutations in acute myeloid leukemia (AML) and correlate with poor prognosis. Receptor tyrosine kinase inhibitors targeting FLT3 have developed as attractive treatment options. Because relapses occur after initial responses, identification of FLT3-ITD–mediated signaling events are important to facilitate novel therapeutic interventions. Here, we have determined the growth-inhibitory and proapototic mechanisms of 2 small molecule inhibitors of FLT3, AG1295 or PKC412, in hematopoietic progenitor cells, human leukemic cell lines, and primary AML cells expressing FLT3-ITD. Inactivation of the PI3-kinase pathway, but not of Ras–mitogen-activated protein (MAP) kinase signaling, was essential to elicit cytotoxic responses. Both compounds induced up-regulation of proapoptotic BH3-only proteins Bim and Puma, and subsequent cell death. However, only silencing of Bim, or its direct transcriptional activator FOXO3a, abrogated apoptosis efficiently. Similar findings were made in bone marrow cells from gene-targeted mice lacking Bim and/or Puma infected with FLT3-ITD and treated with inhibitor, where loss of Puma only provided transient protection from apoptosis, but loss of Bim preserved clonal survival upon FLT3-ITD inhibition.
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Leung, John SM. "Cost-effectiveness of epidermal growth factor receptor-targeting tyrosine kinase inhibitors." Hong Kong Medical Journal 20, no. 5 (October 8, 2014): 465. http://dx.doi.org/10.12809/hkmj144336.
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Yu, Xiangfan, Simei Qiu, Dongshan Sun, Pei Guo, and Quhuan Li. "Comparison of Intermolecular Interactions of Irreversible and Reversible Inhibitors with Bruton’s Tyrosine Kinase via Molecular Dynamics Simulations." Molecules 27, no. 21 (November 2, 2022): 7451. http://dx.doi.org/10.3390/molecules27217451.
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Bruton’s tyrosine kinase (BTK) is a key protein from the TEC family and is involved in B-cell lymphoma occurrence and development. Targeting BTK is therefore an effective strategy for B-cell lymphoma treatment. Since previous studies on BTK have been limited to structure-function analyses of static protein structures, the dynamics of conformational change of BTK upon inhibitor binding remain unclear. Here, molecular dynamics simulations were conducted to investigate the molecular mechanisms of association and dissociation of a reversible (ARQ531) and irreversible (ibrutinib) small-molecule inhibitor to/from BTK. The results indicated that the BTK kinase domain was found to be locked in an inactive state through local conformational changes in the DFG motif, and P-, A-, and gatekeeper loops. The binding of the inhibitors drove the outward rotation of the C-helix, resulting in the upfolded state of Trp395 and the formation of the salt bridge of Glu445-Arg544, which maintained the inactive conformation state. Met477 and Glu475 in the hinge region were found to be the key residues for inhibitor binding. These findings can be used to evaluate the inhibitory activity of the pharmacophore and applied to the design of effective BTK inhibitors. In addition, the drug resistance to the irreversible inhibitor Ibrutinib was mainly from the strong interaction of Cys481, which was evidenced by the mutational experiment, and further confirmed by the measurement of rupture force and rupture times from steered molecular dynamics simulation. Our results provide mechanistic insights into resistance against BTK-targeting drugs and the key interaction sites for the development of high-quality BTK inhibitors. The steered dynamics simulation also offers a means to rapidly assess the binding capacity of newly designed inhibitors.
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Weatherald, Jason, Louise Bondeelle, Marie-Camille Chaumais, Christophe Guignabert, Laurent Savale, Xavier Jaïs, Olivier Sitbon, et al. "Pulmonary complications of Bcr-Abl tyrosine kinase inhibitors." European Respiratory Journal 56, no. 4 (June 11, 2020): 2000279. http://dx.doi.org/10.1183/13993003.00279-2020.
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Tyrosine kinase inhibitors (TKIs) targeting the Bcr-Abl oncoprotein revolutionised the treatment of chronic myelogenous leukaemia. Following the success of imatinib, second- and third-generation molecules were developed. Different profiles of kinase inhibition and off-target effects vary between TKIs, which leads to a broad spectrum of potential toxicities.Pulmonary complications are most frequently observed with dasatinib but all other Bcr-Abl TKIs have been implicated. Pleural effusions are the most frequent pulmonary complication of TKIs, usually associated with dasatinib and bosutinib. Pulmonary arterial hypertension is an uncommon but serious complication of dasatinib, which is often reversible upon discontinuation. Bosutinib and ponatinib have also been associated with pulmonary arterial hypertension, while imatinib has not. Rarely, interstitial lung disease has been associated with TKIs, predominantly with imatinib.Mechanistically, dasatinib affects maintenance of normal pulmonary endothelial integrity by generating mitochondrial oxidative stress, inducing endothelial apoptosis and impairing vascular permeability in a dose-dependent manner. The mechanisms underlying other TKI-related complications are largely unknown. Awareness and early diagnosis of the pulmonary complications of Bcr-Abl TKIs is essential given their seriousness, potential reversibility, and impact on future treatment options for the underlying chronic myelogenous leukaemia.
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Wei, Jia, Ling Ma, Chenglong Li, Christopher R. Pierson, Jonathan L. Finlay, and Jiayuh Lin. "Targeting Upstream Kinases of STAT3 in Human Medulloblastoma Cells." Current Cancer Drug Targets 19, no. 7 (August 2, 2019): 571–82. http://dx.doi.org/10.2174/1568009618666181016165604.
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Background:Medulloblastoma is the most common malignant brain tumor in children. Despite improvement in overall survival rate, it still lacks an effective targeted treatment strategy. The Janus family of cytoplasmic tyrosine kinases (JAKs) and Src kinases, upstream protein kinases of signal transducer and activator of transcription 3 (STAT3), play important roles in medulloblastoma pathogenesis and therefore represent potential therapeutic targets.Methods:In this report, we examined the inhibitory efficacy of the JAK1/2 inhibitor, ruxolitinib, the JAK3 inhibitor, tofacitinib and two Src inhibitors, KX2-391 and dasatinib.Results:These small molecule drugs significantly reduce cell viability and inhibit cell migration and colony formation in human medulloblastoma cells in vitro. Src inhibitors have more potent efficacy than JAK inhibitors in inhibiting medulloblastoma cell migration ability. The Src inhibitors can inhibit both phosphorylation of STAT3 and Src while JAK inhibitors reduce JAK/STAT3 phosphorylation. We also investigated the combined effect of the Src inhibitor, dasatinib with cisplatin. The results show that dasatinib exerts synergistic effects with cisplatin in human medulloblastoma cells through the inhibition of STAT3 and Src.Conclusion:Our results suggest that the small molecule inhibitors of STAT3 upstream kinases, ruxolitinib, tofacitinib, KX2-391, and dasatinib could be novel and attractive candidate drugs for the treatment of human medulloblastoma.
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Lv, Jiahui, Jingde Wu, Feng He, Ying Qu, Qiuqiong Zhang, and Chenggong Yu. "Development of Bruton’s Tyrosine Kinase Inhibitors for Rheumatoid Arthritis." Current Medicinal Chemistry 25, no. 42 (February 6, 2019): 5847–59. http://dx.doi.org/10.2174/0929867325666180316121951.
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Rheumatoid Arthritis (RA) is a chronic autoimmune disease and becomes one of the major causes of disability and work force loss. The presence of abnormal B cell and autoantibodies produced by most RA patients, primarily ACPA and RF, indicate that the function of B cell was involved in the development of RA disease. Accordingly, the drug targeting B cell has become a hot spot in the treatment of RA. Studies have shown that Bruton's tyrosine kinase (BTK) is involved in the regulation of B cell proliferation and activation process. Some small molecule BTK inhibitors have shown excellent inhibition in biological activity analysis and animal models. Therefore, this review will briefly introduce BTK and its role in cell signaling and overview recent progress of BTK inhibitors for RA treatment.
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Hu, Chunqi, and Xiaowu Dong. "Cysteine-targeted Irreversible Inhibitors of Tyrosine Kinases and Key Interactions." Current Medicinal Chemistry 26, no. 31 (November 19, 2019): 5811–24. http://dx.doi.org/10.2174/0929867325666180713124223.
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Tyrosine kinases are a subgroup of a large class of protein kinases that transfer phosphate groups from ATP to various amino acid residues. By phosphorylating the tyrosine residues, the tyrosine kinases are responsible for the activation of various proteins through signal transduction cascades, which serves as a ubiquitous mechanism of cell signaling. The frequent success of many tyrosine kinase inhibitors (TKIs) in clinical success and diseasecausing mutations in protein kinases suggests that a large number of kinases may represent therapeutically relevant targets. To date, most of the clinical and preclinical TKIs are ATPcompetitive non-covalent inhibitors, which achieve their selectivity by recognizing the unique features of specific protein kinases. Of growing interest now in the scientific community is the development of irreversible inhibitors that form covalent bonds with cysteines or other nucleophilic residues in the ATP binding pocket. Irreversible TKIs have many potential advantages including prolonged pharmacodynamics, reasonable compound design suitability, high potency, and the ability to validate pharmacological specificity by mutations in reactive cysteine residues. Here, we review recent efforts to develop cysteine-targeting irreversible TKIs and to discuss their patterns of configuration that identify adenosine triphosphate binding pockets and their biological activities.