Статті в журналах: "Protein targeted lead molecule"

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Hyun, Soonsil, and Dongyun Shin. "Chemical-Mediated Targeted Protein Degradation in Neurodegenerative Diseases." Life 11, no. 7 (June 24, 2021): 607. http://dx.doi.org/10.3390/life11070607.

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Neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease, are a class of diseases that lead to dysfunction of cognition and mobility. Aggregates of misfolded proteins such as β-amyloid, tau, α-synuclein, and polyglutamates are known to be among the main causes of neurodegenerative diseases; however, they are considered to be some of the most challenging drug targets because they cannot be modulated by conventional small-molecule agents. Recently, the degradation of target proteins by small molecules has emerged as a new therapeutic modality and has garnered the interest of the researchers in the pharmaceutical industry. Bifunctional molecules that recruit target proteins to a cellular protein degradation machinery, such as the ubiquitin–proteasome system and autophagy–lysosome pathway, have been designed. The representative targeted protein degradation technologies include molecular glues, proteolysis-targeting chimeras, hydrophobic tagging, autophagy-targeting chimeras, and autophagosome-tethering compounds. Although these modalities have been shown to degrade many disease-related proteins, such technologies are expected to be potentially important for neurogenerative diseases caused by protein aggregation. Herein, we review the recent progress in chemical-mediated targeted protein degradation toward the discovery of drugs for neurogenerative diseases.

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Giardina, Sarah F., Elena Valdambrini, Michael Peel, Manny D. Bacolod, Mace L. Rothenberg, Richard B. Lanman, J. David Warren, and Francis Barany. "Cure-PROs: Next-generation targeted protein degraders." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): e15101-e15101. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e15101.

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e15101 Background: Many proteins, including transcription factors and scaffolding proteins, are not amenable to targeting by traditional small molecule inhibitors due to the lack of a well-defined binding pocket or active site. Proteolysis-Targeting Chimeras (PROTACs) are a new class of hetero-bifunctional molecules that bind both a target protein and an E3 ubiquitin ligase, bringing the two into proximity for appending ubiquitin, and subsequently marking the target protein for proteasomal degradation. Currently, thirteen PROTACs are in clinical trials for oncology indications. However, the clinical utility of PROTACs is challenged by their large size and long development timelines. Also, resistance mutations in the E3 ligase or transporter overexpression inevitably evolve. Thus, a new platform for small-molecule degraders that enables ultra-rapid drug development timelines, efficient cellular uptake, and can be developed to overcome innate and acquired drug resistance is needed. Methods: Coferons, developed in our laboratory, are small molecules that self-assemble upon binding to a target, where they form reversible covalent dimers through bio-orthogonal linker chemistries. We have combined features of the Coferon platform and PROTACs to generate CURE-PROs (Combinatorial Ubiquitination REal-time PROteolysis), consisting of one target protein ligand and one E3 ligase ligand that form reversible heterodimers that lead to targeted protein degradation within cells. By modifying known ligands for BRD4, and the E3 ubiquitin ligases Cereblon, VHL, and MDM2, with linkers able to reversibly join the BRD4 to the ligase ligands, we synthesized libraries of CURE-PRO monomers that can be combined to create thousands of CURE-PRO dimer combinations. We explored whether this platform could yield meaningful BRD4 degradation in vitro and in vivo. Results: Rapid combinatorial cell-based screening identified several BRD4-E3 ligase CURE-PRO combinations that induced greater than 50% BRD4 degradation, with the most promising CURE-PRO pairs achieving more than 95% protein degradation. Consistent with a PROTAC mechanism-of-action, successful CURE-PRO combinations confirmed significant protein degradation which was inhibited by proteasome inhibitors or competition with parent ligands. Significant BRD4 degradation was also observed in mice bearing bilateral human xenograft tumors, confirming CURE-PRO proof-of-mechanism in vivo. Conclusions: The combinatorial nature of our platform has the potential to significantly reduce synthesis time and effort to identify the optimal linker length and E3 ligase for each target protein. The CURE-PRO platform consists of expanding libraries of monomers for both additional oncoprotein targets as well as E3 ligases, which can be redeployed to shorten lead development timelines.

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Musielak, Bogdan, Weronika Janczyk, Ismael Rodriguez, Jacek Plewka, Dominik Sala, Katarzyna Magiera-Mularz, and Tad Holak. "Competition NMR for Detection of Hit/Lead Inhibitors of Protein–Protein Interactions." Molecules 25, no. 13 (July 1, 2020): 3017. http://dx.doi.org/10.3390/molecules25133017.

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Screening for small-molecule fragments that can lead to potent inhibitors of protein–protein interactions (PPIs) is often a laborious step as the fragments cannot dissociate the targeted PPI due to their low μM–mM affinities. Here, we describe an NMR competition assay called w-AIDA-NMR (weak-antagonist induced dissociation assay-NMR), which is sensitive to weak μM–mM ligand–protein interactions and which can be used in initial fragment screening campaigns. By introducing point mutations in the complex’s protein that is not targeted by the inhibitor, we lower the effective affinity of the complex, allowing for short fragments to dissociate the complex. We illustrate the method with the compounds that block the Mdm2/X-p53 and PD-1/PD-L1 oncogenic interactions. Targeting the PD-/PD-L1 PPI has profoundly advanced the treatment of different types of cancers.

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Thomas, Bedwyr ab Ion, H. Lois Lewis, D. Heulyn Jones, and Simon E. Ward. "Central Nervous System Targeted Protein Degraders." Biomolecules 13, no. 8 (July 25, 2023): 1164. http://dx.doi.org/10.3390/biom13081164.

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Diseases of the central nervous system, which once occupied a large component of the pharmaceutical industry research and development portfolio, have for many years played a smaller part in major pharma pipelines—primarily due to the well cited challenges in target validation, valid translational models, and clinical trial design. Unfortunately, this decline in research and development interest has occurred in tandem with an increase in the medical need—in part driven by the success in treating other chronic diseases, which then results in a greater overall longevity along with a higher prevalence of diseases associated with ageing. The lead modality for drug agents targeting the brain remains the traditionally small molecule, despite potential in gene-based therapies and antibodies, particularly in the hugely anticipated anti-amyloid field, clearly driven by the additional challenge of effective distribution to the relevant brain compartments. However, in recognition of the growing disease burden, advanced therapies are being developed in tandem with improved delivery options. Hence, methodologies which were initially restricted to systemic indications are now being actively explored for a range of CNS diseases—an important class of which include the protein degradation technologies.

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Das, Debanu, Matthew Duncton, Patricia Pellicena, Ashley Deacon, David Wilson, and Millie Georgiadis. "Development of a DNA damage response (DDR) therapeutics platform for oncology." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e15036-e15036. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e15036.

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e15036 Background: Cancer cells respond to increases in DNA damage by deploying their DNA damage response (DDR) pathways. We are building a platform for the discovery and development of target-specific DDR therapeutics, including small molecule inhibitors and targeted protein degradation warheads, founded on fragment- and structure-based drug discovery. Methods: Our DDR platform, which includes hit-to-lead, lead optimization and candidate selection, starts with hit generation from a new technology that uses high-throughput protein X-ray crystallography to directly screen compound libraries. Our hit generation process produces empirical evidence of direct target engagement. The elucidation of high-quality ligand-bound 3D structures reveals the location and pose of the ligand and details of the protein-ligand interactions. Thus we can predict the structure-function consequences of the hit molecule engagement, which sets the stage for rapid assessment of synthetic tractability and intellectual property. After hit identification, we apply a multi-pronged approach in hit-to-lead conversion and lead optimization using iterative biophysical and biochemical assays, coupled with crystallography. We are applying our approach to several new targets in DDR and will present some early progress in this space. Results: Apurinic/apyrimidinic endonuclease 1 (APE1) is the major repair enzyme for abasic sites in DNA and contributes to DNA strand break processing. Many studies have associated increased APE1 levels with enhanced growth, migration, and drug resistance in human tumor cells, and with decreased patient survival. APE1 has been implicated in over 20 human cancers, including glioblastoma, making the protein an attractive target for the development of anticancer therapeutics. Despite intensive effort, there are no clinical endonuclease inhibitors of APE1. We have identified 25 diverse small molecule fragments that bind to APE1 at two distinct sites, including the endonuclease site. Pol eta (or PolH) is a DNA polymerase implicated, among other things, in the development of cisplatin resistance in a subset of ovarian cancers. In our quest to develop PolH inhibitors, we have identified 5 diverse fragments that bind to two distinct sites in the polymerase including a new potential allosteric site. Our results on APE1 and PolH represent the first known cases of crystal structures of small molecules bound to these proteins. Flap endonuclease (FEN1) is implicated in several cancers including for example ER/tamoxifen-resistant breast cancer. We are developing a targeted protein degradation approach using PROTACs (Proteolysis-Targeting Chimeras) toward the development of novel therapeutics against FEN1. Conclusions: Our results will help us develop small molecule inhibitors and targeted protein degradation against DDR targets that may be effective as single therapies or be used to make existing therapies more effective.

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Milosevic, Ivana. "Resistance to targeted therapy in chronic lymphocytic leukemia." Medical review 75, Suppl. 1 (2022): 57–61. http://dx.doi.org/10.2298/mpns22s1057m.

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Targeted therapy with inhibitors of cell signaling pathways and inhibitors of anti-apoptotic molecules significantly improved treatment of chronic lymphocytic leukemia. Inhibitors of Bruton?s tyrosine kinase and inhibitors of bcl2 protein showed significant efficacy in either treatment-na?ve or relapsed/refractory patients and in patients with poor risk factors. The majority of patients respond to treatment and have durable remissions, but some of them develop resistance, which leads to clinical relapse. The most frequent cause of resistance is mutations on the binding site of targeted molecules, such as Bruton?s tyrosine kinase mutations in patients treated with ibrutinib or acalabrutinib, or bcl2 mutations in patients treated with venetoclax. There are also alternative mechanisms that can lead to resistance, such as mutations of another molecule in Bruton?s tyrosine kinase signaling pathway, PLCG2, or overexpression of bcl2 protein. These mutations have been detected several months before clinical sings of relapse, and therefore could serve as predictive markers of treatment failure. When resistance to inhibitors of Bruton?s tyrosine kinase occurs, treatment with bcl2 inhibitors will be effective in most cases, and vice versa. Other strategies for overcoming resistance to inhibitors of Bruton?s tyrosine kinase or bcl2 protein are treatment with PI3K inhibitors, second and third generation Bruton?s tyrosine kinase inhibitors, bispecific antiCD3/CD19 antibodies, chimeric antigen receptor T-cells and allogenic stem cell transplantation. Several molecules, which can inhibit or degrade different signaling targets in chronic lymphocytic leukemia cells, are currently under investigation, and they could be effective in patients resistant to inhibitors of Bruton?s tyrosine kinase and bcl2 protein.

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Qokoyi, Ndibonani Kebonang, Priscilla Masamba, and Abidemi Paul Kappo. "Proteins as Targets in Anti-Schistosomal Drug Discovery and Vaccine Development." Vaccines 9, no. 7 (July 8, 2021): 762. http://dx.doi.org/10.3390/vaccines9070762.

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Proteins hardly function in isolation; they form complexes with other proteins or molecules to mediate cell signaling and control cellular processes in various organisms. Protein interactions control mechanisms that lead to normal and/or disease states. The use of competitive small molecule inhibitors to disrupt disease-relevant protein–protein interactions (PPIs) holds great promise for the development of new drugs. Schistosome invasion of the human host involves a variety of cross-species protein interactions. The pathogen expresses specific proteins that not only facilitate the breach of physical and biochemical barriers present in skin, but also evade the immune system and digestion of human hemoglobin, allowing for survival in the host for years. However, only a small number of specific protein interactions between the host and parasite have been functionally characterized; thus, in-depth understanding of the molecular mechanisms of these interactions is a key component in the development of new treatment methods. Efforts are now focused on developing a schistosomiasis vaccine, as a proposed better strategy used either alone or in combination with Praziquantel to control and eliminate this disease. This review will highlight protein interactions in schistosomes that can be targeted by specific PPI inhibitors for the design of an alternative treatment to Praziquantel.

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Olsen, Sarah Naomi, Laura Godfrey, James P. Healy, Charles Hatton, and Scott A. Armstrong. "Abstract 681: Targeted MLL-AF9 degradation is phenocopied by combined DOT1L and Menin inhibition." Cancer Research 82, no. 12_Supplement (June 15, 2022): 681. http://dx.doi.org/10.1158/1538-7445.am2022-681.

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Abstract MLL1 (KMT2A) translocations lead to aberrant expression of stem cell associated gene programs in hematopoietic cells producing a particularly aggressive subtype of leukemia, namely MLL-rearranged acute myeloid and lymphoblastic leukemia (AML and ALL, respectively). In pediatric leukemia, the most common rearrangement is the t(9; 11) (p22; q23) reciprocal translocation, which results in the expression of the MLL-AF9 fusion gene. Since the MLL-AF9 rearrangement does not lead to direct activation of an enzyme, small molecule drug discovery remains challenging and despite decades of research on MLL-rearranged leukemia, we have been limited by the inability of acutely assessing the consequences of direct MLL-AF9 inactivation in relevant model systems. By coupling rapid PROTAC-mediated degradation of the oncogenic MLL-AF9 fusion protein with genome-wide gene expression and chromatin analyses we have now been able to identify the immediate transcriptional and chromatin state consequences of MLL-AF9 degradation. Specifically, we have established a core set of MLL-AF9 target genes whose expression changes within minutes of MLL-AF9 degradation. These rapid expression changes are mediated by changes in productive RNA Polymerase II elongation and increased RNA Polymerase II pausing. At later timepoints, degradation of the fusion protein also induces loss of an active chromatin landscape at MLL-AF9 target genes, characterized by loss of MLL-AF9 associated proteins and activating histone modifications. These insights improve our mechanistic understanding of how MLL-AF9 mediates chromatin remodeling and leukemogenesis, while also helping us evaluate small molecule inhibitors of epigenetic mechanisms that target the MLL-AF9 protein complex. Specifically, we investigated how degradation of MLL-AF9 compares to enzymatic inhibition of DOT1L or inhibition of the MENIN-MLL interaction. Interestingly, both DOT1L and MENIN inhibitors fell short when comparing their effects to MLL-AF9 degradation and only combined DOT1L/MENIN inhibition induced global MLL-AF9 destabilization on chromatin, thus disrupting the full MLL-AF9 directed epigenetic and transcriptional program. Ultimately, we were able to confirm these findings in a patient-derived xenograft model in vivo, where only the combination was able to significantly prolong leukemia free survival. In summary, our studies establish the cellular and molecular consequences of targeted degradation of the MLL-AF9 fusion oncoprotein and help improve our understanding of small molecule inhibitors of epigenetic mechanisms as cancer therapies. Citation Format: Sarah Naomi Olsen, Laura Godfrey, James P. Healy, Charles Hatton, Scott A. Armstrong. Targeted MLL-AF9 degradation is phenocopied by combined DOT1L and Menin inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 681.

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Khattri, Ram B., Daniel L. Morris, Stephanie M. Bilinovich, Erendra Manandhar, Kahlilah R. Napper, Jacob W. Sweet, David A. Modarelli, and Thomas C. Leeper. "Identifying Ortholog Selective Fragment Molecules for Bacterial Glutaredoxins by NMR and Affinity Enhancement by Modification with an Acrylamide Warhead." Molecules 25, no. 1 (December 30, 2019): 147. http://dx.doi.org/10.3390/molecules25010147.

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Illustrated here is the development of a new class of antibiotic lead molecules targeted at Pseudomonas aeruginosa glutaredoxin (PaGRX). This lead was produced to (a) circumvent efflux-mediated resistance mechanisms via covalent inhibition while (b) taking advantage of species selectivity to target a fundamental metabolic pathway. This work involved four components: a novel workflow for generating protein specific fragment hits via independent nuclear magnetic resonance (NMR) measurements, NMR-based modeling of the target protein structure, NMR guided docking of hits, and synthetic modification of the fragment hit with a vinyl cysteine trap moiety, i.e., acrylamide warhead, to generate the chimeric lead. Reactivity of the top warhead-fragment lead suggests that the ortholog selectivity observed for a fragment hit can translate into a substantial kinetic advantage in the mature warhead lead, which bodes well for future work to identify potent, species specific drug molecules targeted against proteins heretofore deemed undruggable.

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Yang, Kylie, Jacek L. Kolanowski, and Elizabeth J. New. "Mitochondrially targeted fluorescent redox sensors." Interface Focus 7, no. 2 (April 6, 2017): 20160105. http://dx.doi.org/10.1098/rsfs.2016.0105.

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The balance of oxidants and antioxidants within the cell is crucial for maintaining health, and regulating physiological processes such as signalling. Consequently, imbalances between oxidants and antioxidants are now understood to lead to oxidative stress, a physiological feature that underlies many diseases. These processes have spurred the field of chemical biology to develop a plethora of sensors, both small-molecule and fluorescent protein-based, for the detection of specific oxidizing species and general redox balances within cells. The mitochondrion, in particular, is the site of many vital redox reactions. There is therefore a need to target redox sensors to this particular organelle. It has been well established that targeting mitochondria can be achieved by the use of a lipophilic cation-targeting group, or by utilizing natural peptidic mitochondrial localization sequences. Here, we review how these two approaches have been used by a number of researchers to develop mitochondrially localized fluorescent redox sensors that are already proving useful in providing insights into the roles of reactive oxygen species in the mitochondria.

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Li, Yan, Yi Jia, Xiao-Lin Wang, Hai Shang, and Yu Tian. "Protein-Targeted Degradation Agents Based on Natural Products." Pharmaceuticals 16, no. 1 (December 28, 2022): 46. http://dx.doi.org/10.3390/ph16010046.

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Natural products are an important source of drug lead compounds, and natural products with significant biological activity are constantly being discovered and used in clinical practice. At present, natural products play an important role in the targeted therapy of cancer, cardiovascular and cerebrovascular diseases, nervous system diseases, and autoimmune diseases. Meanwhile, in recent years, the rise of protein-targeted degradation technologies, such as proteolysis-targeting chimeras (PROTACs) and molecular glues, has provided a new solution for drug resistance caused by clinical molecular-targeting drugs. It is noteworthy that natural products and their derivatives, as important components of PROTACs and molecular glues, play an important role in the development of protein-targeting drugs. Hence, this review summarized the protein-targeted degradation agents based on natural products, such as PROTACs and molecular glues. More natural products with the potential to be used in the development of PROTACs and molecular glues as targeted protein degradation agents are still being investigated.

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Rayevsky, O. V., O. M. Demchyk, P. A. Karpov, S. P. Ozheredov, S. I. Spivak, A. I. Yemets та Ya B. Blume. "Structure-based virtual screening for new lead compounds targeted Plasmodium α-tubulin". Faktori eksperimental'noi evolucii organizmiv 28 (31 серпня 2021): 135–39. http://dx.doi.org/10.7124/feeo.v28.1389.

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Aim. Search for new dinitroaniline and phosphorothioamide compounds, capable of selective binding with Plasmodium α-tubulin, affecting its mitotic apparatus. Methods. Structural biology methods of computational prediction of protein-ligand interaction: molecular docking, molecular dynamics and pharmacophore analysis. Selection of compounds based on pharmacophore characteristics and virtual screening results. Results. The protocol and required structural conditions for target (α-tubulin of P. falciparum) preparation and correct modeling of the ligand-protein interaction (docking and virtual screening) were developed. The generalized pharmacophore model of ligand-protein interaction and key functional groups of ligands responsible for specific binding were identified. Conclusions. Based on results of virtual screening, 22 commercial compounds were selected. Identified compounds proposed as potential inhibitors of Plasmodium mitotic machinery and the base of new antimalarial drugs. Keywords: malaria, Plasmodium, intermolecular interaction, dinitroaniline derived, phosphorothioamidate derived.

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Roos, Martina M., Michelle Li, Pang Amara, and John P. Chute. "Pharmacologic Targeting of LIN28/Let-7 in Acute Myeloid Leukemia." Blood 132, Supplement 1 (November 29, 2018): 4072. http://dx.doi.org/10.1182/blood-2018-99-119982.

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Abstract Acute myeloid leukemia (AML) is a genetically heterogeneous malignancy with high relapse rates and mortality due to the outgrowth of chemotherapy-resistant leukemic stem cells (LSCs). Thus, the development of novel therapeutic strategies capable of eradicating human AML represents a major area of unmet medical need. The RNA binding protein, LIN28, is a known driver of many cancer stem cells, AML included, wherein overexpression of LIN28 correlates with reduced patient survival. LIN28 blocks the function of the let-7 microRNA family, which exert tumor suppressive effects by repressing oncogenes and cell cycle regulators including MYC, RAS and CyclinD. Thus, LIN28 is an attractive mechanistic target for the purpose of inhibiting AML LSCs. Using a targeted high-throughput screen, we identified a class of small molecules which selectively block the LIN28/let-7 interaction (Roos et al., ACS Chem Biol, 2016). Preliminary studies demonstrate that a lead small molecule markedly impairs the proliferation and clonogenic capacity of human AML cell lines and primary patient AML samples. In vivo, systemic administration of a lead small molecule LIN28/let-7 inhibitor decreases leukemic tumor burden, reduces LSC numbers and significantly improves animal survival. Mechanistic studies revealed that targeted inhibition of the LIN28/let-7 axis restores let-7 microRNA levels in AML LSCs and subsequently inhibits a panoply of key oncogenic driver genes, including the NF-ĸB pathway, a hallmark for LSC proliferation. Furthermore, AML cell lines and primary patient cells treated with the LIN28/let-7 small molecule inhibitor showed a block at the G1/S phase interface and significantly decreased cell cycle progression. Consequently, LIN28/let-7 inhibition leads to LSC differentiation and ultimately leukemic cell death. In summary, we demonstrate for the first time the drugability of the LIN28/let-7 axis in vivo and reveal a novel pharmacological means to suppress a multitude of oncogenic driver genes in human AML. These results suggest that small molecule inhibition of LIN28/let-7 has high therapeutic potential as a new class of targeted therapies for AML. Disclosures No relevant conflicts of interest to declare.

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Angelbello, Alicia J., Suzanne G. Rzuczek, Kendra K. Mckee, Jonathan L. Chen, Hailey Olafson, Michael D. Cameron, Walter N. Moss, Eric T. Wang, and Matthew D. Disney. "Precise small-molecule cleavage of an r(CUG) repeat expansion in a myotonic dystrophy mouse model." Proceedings of the National Academy of Sciences 116, no. 16 (March 29, 2019): 7799–804. http://dx.doi.org/10.1073/pnas.1901484116.

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Myotonic dystrophy type 1 (DM1) is an incurable neuromuscular disorder caused by an expanded CTG repeat that is transcribed into r(CUG)exp. The RNA repeat expansion sequesters regulatory proteins such as Muscleblind-like protein 1 (MBNL1), which causes pre-mRNA splicing defects. The disease-causing r(CUG)exp has been targeted by antisense oligonucleotides, CRISPR-based approaches, and RNA-targeting small molecules. Herein, we describe a designer small molecule, Cugamycin, that recognizes the structure of r(CUG)exp and cleaves it in both DM1 patient-derived myotubes and a DM1 mouse model, leaving short repeats of r(CUG) untouched. In contrast, oligonucleotides that recognize r(CUG) sequence rather than structure cleave both long and short r(CUG)-containing transcripts. Transcriptomic, histological, and phenotypic studies demonstrate that Cugamycin broadly and specifically relieves DM1-associated defects in vivo without detectable off-targets. Thus, small molecules that bind and cleave RNA have utility as lead chemical probes and medicines and can selectively target disease-causing RNA structures to broadly improve defects in preclinical animal models.

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Schäfer, Mirijam, Marie Luise Semmler, Thoralf Bernhardt, Tobias Fischer, Vinodh Kakkassery, Robert Ramer, Martin Hein, et al. "Small Molecules in the Treatment of Squamous Cell Carcinomas: Focus on Indirubins." Cancers 13, no. 8 (April 7, 2021): 1770. http://dx.doi.org/10.3390/cancers13081770.

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Skin cancers are the most common malignancies in the world. Among the most frequent skin cancer entities, squamous cell carcinoma (SCC) ranks second (~20%) after basal cell carcinoma (~77%). In early stages, a complete surgical removal of the affected tissue is carried out as standard therapy. To treat advanced and metastatic cancers, targeted therapies with small molecule inhibitors are gaining increasing attention. Small molecules are a heterogeneous group of protein regulators, which are produced by chemical synthesis or fermentation. The majority of them belong to the group of receptor tyrosine kinase inhibitors (RTKIs), which specifically bind to certain RTKs and directly influence the respective signaling pathway. Knowledge of characteristic molecular alterations in certain cancer entities, such as SCC, can help identify tumor-specific substances for targeted therapies. Most frequently, altered genes in SCC include TP53, NOTCH, EGFR, and CCND1. For example, the gene CCND1, which codes for cyclin D1 protein, is upregulated in nearly half of SCC cases and promotes proliferation of affected cells. A treatment with the small molecule 5′-nitroindirubin-monoxime (INO) leads to inhibition of cyclin D1 and thus inhibition of proliferation. As a component of Danggui Longhui Wan, a traditional Chinese medicine, indirubins are used to treat chronic diseases and have been shown to inhibit inflammatory reactions. Indirubins are pharmacologically relevant small molecules with proapoptotic and antiproliferative activity. In this review, we discuss the current literature on indirubin-based small molecules in cancer treatment. A special focus is on the molecular biology of squamous cell carcinomas, their alterations, and how these are rendered susceptible to indirubin-based small molecule inhibitors. The potential molecular mechanisms of the efficacy of indirubins in killing SCC cells will be discussed as well.

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Shen, Jingshi, Eric Davis, and Charles Dinarello. "Haploid genetic dissection of immune molecule trafficking (TECH1P.836)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 69.4. http://dx.doi.org/10.4049/jimmunol.192.supp.69.4.

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Abstract To perform their expected functions, immune molecules must be targeted to specific cellular compartments such as the plasma membrane. Improper protein targeting can lead to major forms of immune disease such as immunodeficiency and persistent inflammation. Our group developed a novel haploid genetics approach in order to unravel protein targeting on a genome-wide scale. We take advantage of human myeloid cell lines (e.g. KBM7 and HAP1) that exhibit a haploid karyotype. Retroviral insertional mutagenesis of these cells offers an efficient method to generate a library of mutant cells with complete disruption of specific genes. After selections of desired phenotypes (e.g., mislocalization of a protein), the retroviral insertion sites of the mutant clones can be mapped by deep sequencing. We have used this haploid genetics approach to characterize the plasma membrane protein CD59, a key player in the complement system. We identified ~20 genes involved in the biosynthesis, maturation, and trafficking of CD59. These genes are involved in GPI lipid synthesis, oligosaccharide modification, as well as protein trafficking at both the early and late stages of the secretory pathway. This haploid genetic screen provides the first genome-wide map of a complement protein. Many factors identified in the screen represent novel components of the complement system, and may serve as therapeutic targets for treating immune disorders.

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Chen, Jianlin, Xiaorong Liu, and Jianhan Chen. "Targeting Intrinsically Disordered Proteins through Dynamic Interactions." Biomolecules 10, no. 5 (May 11, 2020): 743. http://dx.doi.org/10.3390/biom10050743.

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Intrinsically disordered proteins (IDPs) are over-represented in major disease pathways and have attracted significant interest in understanding if and how they may be targeted using small molecules for therapeutic purposes. While most existing studies have focused on extending the traditional structure-centric drug design strategies and emphasized exploring pre-existing structure features of IDPs for specific binding, several examples have also emerged to suggest that small molecules could achieve specificity in binding IDPs and affect their function through dynamic and transient interactions. These dynamic interactions can modulate the disordered conformational ensemble and often lead to modest compaction to shield functionally important interaction sites. Much work remains to be done on further elucidation of the molecular basis of the dynamic small molecule–IDP interaction and determining how it can be exploited for targeting IDPs in practice. These efforts will rely critically on an integrated experimental and computational framework for disordered protein ensemble characterization. In particular, exciting advances have been made in recent years in enhanced sampling techniques, Graphic Processing Unit (GPU)-computing, and protein force field optimization, which have now allowed rigorous physics-based atomistic simulations to generate reliable structure ensembles for nontrivial IDPs of modest sizes. Such de novo atomistic simulations will play crucial roles in exploring the exciting opportunity of targeting IDPs through dynamic interactions.

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Yin, Xiaoyan, Subha Subramanian, Shih-Jen Hwang, Christopher J. O’Donnell, Caroline S. Fox, Paul Courchesne, Pieter Muntendam, et al. "Protein Biomarkers of New-Onset Cardiovascular Disease." Arteriosclerosis, Thrombosis, and Vascular Biology 34, no. 4 (April 2014): 939–45. http://dx.doi.org/10.1161/atvbaha.113.302918.

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Objective— Incorporation of novel plasma protein biomarkers may improve current models for prediction of atherosclerotic cardiovascular disease (ASCVD) risk. Approach and Results— We used discovery mass spectrometry (MS) to determine plasma concentrations of 861 proteins in 135 myocardial infarction (MI) cases and 135 matched controls. Then, we measured 59 markers by targeted MS in 336 ASCVD case–control pairs. Associations with MI or ASCVD were tested in single-marker and multiple-marker analyses adjusted for established ASCVD risk factors. Twelve single markers from discovery MS were associated with MI incidence (at P <0.01), adjusting for clinical risk factors. Seven proteins in aggregate (cyclophilin A, cluster of differentiation 5 molecule [CD5] antigen-like, cell-surface glycoprotein mucin cell surface associated protein 18 [MUC-18], collagen-α 1 [XVIII] chain, salivary α-amylase 1, C-reactive protein, and multimerin-2) were highly associated with MI ( P <0.0001) and significantly improved its prediction compared with a model with clinical risk factors alone (C-statistic of 0.71 versus 0.84). Through targeted MS, 12 single proteins were predictors of ASCVD (at P <0.05) after adjusting for established risk factors. In multiple-marker analyses, 4 proteins in combination (α-1–acid glycoprotein 1, paraoxonase 1, tetranectin, and CD5 antigen-like) predicted incident ASCVD ( P <0.0001) and moderately improved the C-statistic from the model with clinical covariates alone (C-statistic of 0.69 versus 0.73). Conclusions— Proteomics profiling identified single- and multiple-marker protein panels that are associated with new-onset ASCVD and may lead to a better understanding of underlying disease mechanisms. Our findings include many novel protein biomarkers that, if externally validated, may improve risk assessment for MI and ASCVD.

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Beaton, Nigel, Roland Bruderer, Yuehan Feng, Jagat Adhikari, Ivan Cornella-Taracido, and Lukas Reiter. "Abstract 2024: High resolution limited proteolysis (HR-LiP), a novel structural proteomics approach for the prediction of small molecule-protein binding events." Cancer Research 83, no. 7_Supplement (April 4, 2023): 2024. http://dx.doi.org/10.1158/1538-7445.am2023-2024.

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Abstract High resolution profiling of drug-protein interactions and binding mechanisms remains a major hurdle during lead selection and optimization. A key milestone in structure-based drug design is compound binding site identification and characterization. Structure-activity relationship (SAR) studies traditionally utilize time and cost intensive techniques such as nuclear magnetic resonance (NMR), x-ray crystallography (X-ray) and cryo-electron microscopy (cryo-EM). To date, hydrogen-deuterium exchange (HDX) is the only mass spectrometry-based approach that has been extensively utilized. Further, SAR studies are often complicated by protein size (large proteins and/or oligomers) and location (membrane proteins), which can lead to protocol adaptations that can introduce artifacts. High resolution limited proteolysis (HR-LiP) is a high-throughput, high-resolution approach based on LiP-Quant that utilizes peptide-level resolution to characterize drug-protein interactions. Two well-characterized drug target proteins, bromodomain-containing protein 4 (BRD4) and transitional endoplasmic reticulum ATPase (VCP), were selected for analysis as they represent both difficult targets for structural biology (size and oligomerization respectively). BRD4 was targeted with a well characterized inhibitor (JQ1), while VCP was investigated for binding with a known autophagy activator. Using HR-LiP we identify the binding site of the BRD4 inhibitor JQ1 in the full-length protein, which is typically too large to be used directly in with conventional methods. Further, we confirm binding of the autophagy activator to VCP at a site known to increase VCP activity. For both compounds tested, our data are in good accordance with orthogonal data obtained by other structural protein approaches including HDX-MS and “click” chemistry-based chemoproteomics. We demonstrate that HR-LiP can be used to dissect small molecule-protein binding events, including compound binding site prediction for protein targets classically considered to be difficult and time intensive. Further, we show that this data can be used to shed light on the biological mechanisms driving a phenotypic response. Given its biological power, broad applicability and ease of implementation, we envision the use of HR-LiP as a routine approach for target validation and lead optimization in small molecule drug discovery pipelines. Citation Format: Nigel Beaton, Roland Bruderer, Yuehan Feng, Jagat Adhikari, Ivan Cornella-Taracido, Lukas Reiter. High resolution limited proteolysis (HR-LiP), a novel structural proteomics approach for the prediction of small molecule-protein binding events [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2024.

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20

Ajay, Amrendra K., Philip Chu, Poojan Patel, Christa Deban, Chitran Roychowdhury, Radhika Heda, Ahmad Halawi, et al. "High-Throughput/High Content Imaging Screen Identifies Novel Small Molecule Inhibitors and Immunoproteasomes as Therapeutic Targets for Chordoma." Pharmaceutics 15, no. 4 (April 18, 2023): 1274. http://dx.doi.org/10.3390/pharmaceutics15041274.

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Chordomas account for approximately 1–4% of all malignant bone tumors and 20% of primary tumors of the spinal column. It is a rare disease, with an incidence estimated to be approximately 1 per 1,000,000 people. The underlying causative mechanism of chordoma is unknown, which makes it challenging to treat. Chordomas have been linked to the T-box transcription factor T (TBXT) gene located on chromosome 6. The TBXT gene encodes a protein transcription factor TBXT, or brachyury homolog. Currently, there is no approved targeted therapy for chordoma. Here, we performed a small molecule screening to identify small chemical molecules and therapeutic targets for treating chordoma. We screened 3730 unique compounds and selected 50 potential hits. The top three hits were Ribociclib, Ingenol-3-angelate, and Duvelisib. Among the top 10 hits, we found a novel class of small molecules, including proteasomal inhibitors, as promising molecules that reduce the proliferation of human chordoma cells. Furthermore, we discovered that proteasomal subunits PSMB5 and PSMB8 are increased in human chordoma cell lines U-CH1 and U-CH2, confirming that the proteasome may serve as a molecular target whose specific inhibition may lead to better therapeutic strategies for chordoma.

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Kanakaveti, V., P. Anoosha, R. Sakthivel, S. K. Rayala, and M. M. Gromiha. "Influence of Amino Acid Mutations and Small Molecules on Targeted Inhibition of Proteins Involved in Cancer." Current Topics in Medicinal Chemistry 19, no. 6 (May 2, 2019): 457–66. http://dx.doi.org/10.2174/1568026619666190304143354.

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Background:Protein-protein interactions (PPIs) are of crucial importance in regulating the biological processes of cells both in normal and diseased conditions. Significant progress has been made in targeting PPIs using small molecules and achieved promising results. However, PPI drug discovery should be further accelerated with better understanding of chemical space along with various functional aspects.Objective:In this review, we focus on the advancements in computational research for targeted inhibition of protein-protein interactions involved in cancer.Methods:Here, we mainly focused on two aspects: (i) understanding the key roles of amino acid mutations in epidermal growth factor receptor (EGFR) as well as mutation-specific inhibitors and (ii) design of small molecule inhibitors for Bcl-2 to disrupt PPIs.Results:The paradigm of PPI inhibition to date reflect the certainty that inclination towards novel and versatile strategies enormously dictate the success of PPI inhibition. As the chemical space highly differs from the normal drug like compounds the lead optimization process has to be given the utmost priority to ensure the clinical success. Here, we provided a broader perspective on effect of mutations in oncogene EGFR connected to Bcl-2 PPIs and focused on the potential challenges.Conclusion:Understanding and bridging mutations and altered PPIs will provide insights into the alarming signals leading to massive malfunctioning of a biological system in various diseases. Finding rational elucidations from a pharmaceutical stand point will presumably broaden the horizons in future.

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SanthaKumari, Subha Lakshmi Gopalakrishnan Nair, and Samuel GnanaPrakash Vincent. "Identification and molecular characterization of drug targets of methicillin resistant Staphylococcus aureus." Journal of Applied and Natural Science 14, no. 4 (December 19, 2022): 1152–57. http://dx.doi.org/10.31018/jans.v14i4.3693.

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Antimicrobial resistance is a major world health concern and drug-resistant Staphylococcus aureus is a serious threat. Due to the emergence of multidrug-resistant bacterial strains, there is an urgent need to develop novel drug targets to meet the challenge of multidrug-resistant organisms. The main objective of the current study was to determine molecular targets against S. aureus using by computational approach. S. aureus was cultured in brain heart infusion broth medium and MRSA (Methicillin resistant S. aureus) protein was extracted acetone-sodium dodecyl sulfate method. The cell lysate was treated with various antibiotics and proteinase K stable proteins were analyzed. The molecular weight of Geninthiocin-targeted protein of interest in S. aureus ranged from 46 to 50 kDa. A prominent protein band in SDS-PAGE indicated that the protein corresponding 50 kDa was resistant against proteinase K. The SDS-PAGE separated sample was excised and trypsinated, and the peptides were characterized using Nano Liquid Chromatography with tandem mass spectrometry (LC-MS/MS) analysis. Spectrum with clusters of molecular peptides and peptide fragments ranging from 110.0716 to 1002.7093 mass/charge ratio (m/z) were displayed against intensity or relative abundance in the excised gel band. The spectral data from nano LC-MS/MS was subjected to mascot search in the NCBIprot database (taxonomy-bacteria (eubacteria), resulting in seven bacterial proteins. Geninthiocin target proteins were determined against MRSA. To conclude, antibiotic target proteins were identified using a machine learning approach and these targets may have a lot of applications in developing a novel lead molecule against drug-resistant bacteria.

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Hanajima-Ozawa, Miyuki, Takeshi Matsuzawa, Aya Fukui, Shigeki Kamitani, Hiroe Ohnishi, Akio Abe, Yasuhiko Horiguchi, and Masami Miyake. "Enteropathogenic Escherichia coli, Shigella flexneri, and Listeria monocytogenes Recruit a Junctional Protein, Zonula Occludens-1, to Actin Tails and Pedestals." Infection and Immunity 75, no. 2 (November 21, 2006): 565–73. http://dx.doi.org/10.1128/iai.01479-06.

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ABSTRACT Enteropathogenic Escherichia coli, Shigella flexneri, and Listeria monocytogenes induce localized actin polymerization at the cytoplasmic face of the plasma membrane or within the host cytoplasm, creating unique actin-rich structures termed pedestals or actin tails. The process is known to be mediated by the actin-related protein 2 and 3 (Arp2/3) complex, which in these cases acts downstream of neural Wiskott-Aldrich syndrome protein (N-WASP) or of a listerial functional homolog of WASP family proteins. Here, we show that zonula occludens-1 (ZO-1), a protein in the tight junctions of polarized epithelial cells, is recruited to actin tails and pedestals. Immunocytochemical analysis revealed that ZO-1 was stained most in the distal part of the actin-rich structures, and the incorporation was mediated by the proline-rich region of the ZO-1 molecule. The direct clustering of membrane-targeted Nck, which is known to activate the N-WASP-Arp2/3 pathway, triggered the formation of the ZO-1-associated actin tails. The results suggest that the activation of the Arp2/3 complex downstream of N-WASP or a WASP-related molecule is a key to the formation of the particular actin-rich structures that bind with ZO-1. We propose that an analysis of the recruitment on a molecular basis will lead to an understanding of how ZO-1 recognizes a distinctive actin-rich structure under pathophysiological conditions.

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Salha M Tawati, Aisha A Alsfouk, and Asma Alsarrah. "Homology modelling and molecular docking study of TMPRSS2 with small-molecule protease inhibitors to control SARS-CoV-2." International Journal of Research in Pharmaceutical Sciences 13, no. 2 (April 19, 2022): 201–10. http://dx.doi.org/10.26452/ijrps.v13i2.190.

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Due to the urgent need of drugs to control the COVID-19 pandemic, repositioning of already marketed drugs could be a fast and convenient option to identify agents to aid in controlling and treating COVID-19. This work presented a computational work regarding homology modeling and molecular docking of repurposing drugs related to the SARS-CoV-2. We have created a homology model of the cell surface transmembrane protease serine 2 protein (TMPRSS2) in order to investigate and analyze the interactions of already known small-molecules. This study indicates the most active inhibitors, poceprevir, simeprevir and neoandrgrapholide, that can be used further to search for better TMPRSS2 inhibitors. Moreover, we analyzed the most important atomistic connections between these compounds and the modeled protein pockets. This study will focus on TMPRSS2-targeted drugs by comparing the binding mode of approved and experimentally used TMRSS2 inhibitors with other agents with TMPRSS2 inhibitory activity and could potentially inhibit SARS-CoV-2 and therefore could lead to the identification of new agents for further clinical evaluation of SARS-CoV-2 and potential treatment of COVID-19.

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25

Bonilla, Francisco A. "Personalized therapy for common variable immunodeficiency." Allergy and Asthma Proceedings 41, no. 1 (January 1, 2020): 19–25. http://dx.doi.org/10.2500/aap.2020.41.190012.

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Background: Common variable immunodeficiency (CVID) represents a clinical descriptive diagnosis that was defined in the 1970s. Despite the vast increase in knowledge with regard to immune function and genetics, the pathophysiology of this disorder remains poorly understood in the majority of patients (75%); however, recent advances have led to a much clearer understanding of this heterogeneous group of disorders in the remaining 25%. These advances, along with developments in immune modulatory and reconstitution therapies, now permit sophisticated and specific targeting of therapies for individual patients. Methods: A literature review and author experience. Results: For > 50 years, immune globulin therapy has been applied to patients with CVID. There are several options open to patients, including a diversity of products and modes of administration. Stem cell therapy is increasingly applicable in patients with severe immune dysregulation. In some disorders (e.g., lipopolysaccharide-responsive and beige-like anchor protein, and cytotoxic T lymphocyte antigen 4 deficiencies), knowledge of the genetic basis and molecular pathophysiology permit targeted therapy by using small-molecule immune modulators and biologics. Conclusion: In the near future, it is likely that further advances in understanding the pathophysiology of CVID, together with ongoing development of biologics and small-molecule immune modulators will lead to additional targeted therapies for these patients.

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Fricke, Doerte Raphaela, Gang Liu, Hyejin Kim, Pingyuan Wang, Xi Liu, Haiying Chen, Ruixia Ma, Junhai Xu, Jia Zhou, and Qiang Shen. "Abstract 3940: Novel Bax activators for targeted breast cancer therapy." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3940. http://dx.doi.org/10.1158/1538-7445.am2022-3940.

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Abstract Breast cancer is one of the leading causes of cancer-related deaths in American women and the most common cancer in women with more than 280,000 estimated new cases in 2021 in the US. Therefore, there is an urgent need of advanced treatment regimens. Particularly the subgroups of estrogen receptor (ER)-negative breast cancers (ENBC) and the even worse triple-negative breast cancer (TNBC), a subtype of ENBC with a high metastatic potential, are lacking efficient treatment methods. Thus, developing more effective drugs for ENBC/TNCB treatment remains an unmet medical need. The pro-apoptotic protein Bax in active form was shown to be downregulated in most cancers. As a result, the balance between Bax and its antagonist Bcl-2 gets disturbed, thereby leading to dysfunctional apoptotic signaling in favor of cancer cell survival. Hence, drug discovery for Bax activation is a promising approach for developing novel cancer therapies. The small molecules GL0385 and GL0388 were identified from our progenitor molecules including small-molecule Bax activator (SMBA1), CYD-2-11, and CYD-4-61. The CYD compounds specifically target the Ser184 residue of Bax and have shown apoptosis-inducing effects in vitro and in vivo. These lead Bax activators provided proof-of-concept studies while further optimization is imperative to mitigate potential toxicity, leading to the discovery of advanced lead molecules GL0385 and GL0388. Treatment with either GL0385 or GL0388 resulted in significantly decreased cell proliferation in MDA-MB-231, MDA-MB-468, BT549, MDA-MB-453, MCF-7, and MDA-MB-361 cells. Additionally, MDA-MB-231 cells treated with GL0385 or GL0388 showed reduced migration and invasion, compared to control cells. Western blot analysis confirmed increased protein levels of Bax, cleaved PARP, cleaved caspase 3, and cytochrome C. These results demonstrate that GL0385 and GL388 have a significant impact on cancer cell proliferation and cellular motility which are main attributes of metastasizing cells. Additionally, increased expression of apoptosis markers indicates that these compounds may be beneficial to regain the anti-apoptotic/pro-apoptotic balance in breast cancer cells. In vivo, both GL0385 and GL0388 show moderate tumor growth inhibition. Further chemical optimization has achieved additional drug candidates including GL0469. Breast cancer cells treated with GL0469 resulted in significant reduction of cell proliferation. Therefore, GL0385, GL0388, and GL0469 are promising new advanced lead compounds towards the development of effective therapies for breast cancers and other cancers with improved safety profiles. Further investigation is warranted to fully explore their anti-cancer potential and mechanisms of action. This project is supported by DOD Awards W81XWH-17-1-0071 and W81XWH-17-1-0072 to J.Z. and Q.S. Keywords: Bax activators, breast cancer, therapeutics, GL0385, GL0388, GL0469 Citation Format: Doerte Raphaela Fricke, Gang Liu, Hyejin Kim, Pingyuan Wang, Xi Liu, Haiying Chen, Ruixia Ma, Junhai Xu, Jia Zhou, Qiang Shen. Novel Bax activators for targeted breast cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3940.

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Savva, Loukiani, and Savvas N. Georgiades. "Recent Developments in Small-Molecule Ligands of Medicinal Relevance for Harnessing the Anticancer Potential of G-Quadruplexes." Molecules 26, no. 4 (February 5, 2021): 841. http://dx.doi.org/10.3390/molecules26040841.

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G-quadruplexes, a family of tetraplex helical nucleic acid topologies, have emerged in recent years as novel targets, with untapped potential for anticancer research. Their potential stems from the fact that G-quadruplexes occur in functionally-important regions of the human genome, such as the telomere tandem sequences, several proto-oncogene promoters, other regulatory regions and sequences of DNA (e.g., rDNA), as well as in mRNAs encoding for proteins with roles in tumorigenesis. Modulation of G-quadruplexes, via interaction with high-affinity ligands, leads to their stabilization, with numerous observed anticancer effects. Despite the fact that only a few lead compounds for G-quadruplex modulation have progressed to clinical trials so far, recent advancements in the field now create conditions that foster further development of drug candidates. This review highlights biological processes through which G-quadruplexes can exert their anticancer effects and describes, via selected case studies, progress of the last few years on the development of efficient and drug-like G-quadruplex-targeted ligands, intended to harness the anticancer potential offered by G-quadruplexes. The review finally provides a critical discussion of perceived challenges and limitations that have previously hampered the progression of G-quadruplex-targeted lead compounds to clinical trials, concluding with an optimistic future outlook.

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Smith, Kathryn, Andrea Lopez-Arroyo, Jason Berk, Peter Hegan, Peter Nower, Samantha Tice, Aurelie Moutran, et al. "Abstract PR09: KRAS-targeted PROTAC degraders are broadly efficacious against KRAS-dependent tumor models." Molecular Cancer Research 21, no. 5_Supplement (May 1, 2023): PR09. http://dx.doi.org/10.1158/1557-3125.ras23-pr09.

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Abstract KRAS is genomically altered in about one third of all human tumors. Due to its central role in oncogenesis, many attempts have been made in the last four decades to drug mutant KRAS, either directly or indirectly. Despite recent advances in targeting KRAS using small molecule inhibitors, the majority of KRAS alterations do not yet have an existing targeted therapy, and where inhibitors are available, resistance rapidly emerges. Thus, novel approaches to drugging KRAS are needed. Eliminating mutant KRAS using a targeted protein degradation approach may lead to superior efficacy relative to inhibiting the protein. KRAS PROTAC® degraders that selectively target the G12D mutant form of KRAS were identified and profiled in KRAS-dependent cancer models. In vitro, PROTAC degraders targeting the G12D mutant degrade KRAS with picomolar potency, robustly suppress MAPK and PI3K/AKT signaling, induce apoptosis, and have antiproliferative activity that is superior to known inhibitors. These molecules are selective for mutant KRAS G12D, neither degrading wild-type KRAS nor the related isoforms HRAS and NRAS. In vivo, these degraders can eliminate >95% of mutant KRAS from relevant xenograft models, induce apoptosis, and lead to tumor regression. Consistent with the extended pharmacodynamics often observed with PROTAC degraders, a single dose of a G12D PROTAC results in prolonged KRAS degradation and significant pERK suppression up to one week after administration. Combined, these data show that degrading mutant KRAS G12D in tumors is highly efficacious and may have advantages over inhibition, making it an exciting potential new approach for the treatment of KRAS mutant cancers. Citation Format: Kathryn Smith, Andrea Lopez-Arroyo, Jason Berk, Peter Hegan, Peter Nower, Samantha Tice, Aurelie Moutran, Jennifer Pizzano, Amanda Dowtin, Mark Bookbinder, Elizabeth Bortolon, Greg Cadelina, Fazlul Karim, Katie Digianantonio, Miklos Bekes, Jesus Medina. KRAS-targeted PROTAC degraders are broadly efficacious against KRAS-dependent tumor models [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr PR09.

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Simard, Jeffrey R., Linda Lee, Ellen Vieux, Reina Improgo, Trang Tieu, Andrew J. Phillips, Stewart L. Fisher, Roy M. Pollock, and Eunice Park. "High-Throughput Quantitative Assay Technologies for Accelerating the Discovery and Optimization of Targeted Protein Degradation Therapeutics." SLAS DISCOVERY: Advancing the Science of Drug Discovery 26, no. 4 (January 11, 2021): 503–17. http://dx.doi.org/10.1177/2472555220985049.

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The aberrant regulation of protein expression and function can drastically alter cellular physiology and lead to numerous pathophysiological conditions such as cancer, inflammatory diseases, and neurodegeneration. The steady-state expression levels of endogenous proteins are controlled by a balance of de novo synthesis rates and degradation rates. Moreover, the levels of activated proteins in signaling cascades can be further modulated by a variety of posttranslational modifications and protein–protein interactions. The field of targeted protein degradation is an emerging area for drug discovery in which small molecules are used to recruit E3 ubiquitin ligases to catalyze the ubiquitination and subsequent degradation of disease-causing target proteins by the proteasome in both a dose- and time-dependent manner. Traditional approaches for quantifying protein level changes in cells, such as Western blots, are typically low throughput with limited quantification, making it hard to drive the rapid development of therapeutics that induce selective, rapid, and sustained protein degradation. In the last decade, a number of techniques and technologies have emerged that have helped to accelerate targeted protein degradation drug discovery efforts, including the use of fluorescent protein fusions and reporter tags, flow cytometry, time-resolved fluorescence energy transfer (TR-FRET), and split luciferase systems. Here we discuss the advantages and disadvantages associated with these technologies and their application to the development and optimization of degraders as therapeutics.

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Shuttleworth, Stephen, Richard Connors, Jiasheng Fu, Jinqian Liu, Mike Lizarzaburu, Wei Qiu, Rajiv Sharma, Malgorzata Wanska, and Alex Zhang. "Design and Synthesis of Protein Superfamily-Targeted Chemical Libraries for Lead Identification and Optimization." Current Medicinal Chemistry 12, no. 11 (June 1, 2005): 1239–81. http://dx.doi.org/10.2174/0929867054020936.

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Yunes, Sarah A., Jennifer L. S. Willoughby, Julian H. Kwan, Jessica M. Biagi, Niranjana Pokharel, Hang Gyeong Chin, Emily A. York, et al. "Factor quinolinone inhibitors disrupt spindles and multiple LSF (TFCP2)-protein interactions in mitosis, including with microtubule-associated proteins." PLOS ONE 17, no. 6 (June 15, 2022): e0268857. http://dx.doi.org/10.1371/journal.pone.0268857.

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Factor quinolinone inhibitors (FQIs), a first-in-class set of small molecule inhibitors targeted to the transcription factor LSF (TFCP2), exhibit promising cancer chemotherapeutic properties. FQI1, the initial lead compound identified, unexpectedly induced a concentration-dependent delay in mitotic progression. Here, we show that FQI1 can rapidly and reversibly lead to mitotic arrest, even when added directly to mitotic cells, implying that FQI1-mediated mitotic defects are not transcriptionally based. Furthermore, treatment with FQIs resulted in a striking, concentration-dependent diminishment of spindle microtubules, accompanied by a concentration-dependent increase in multi-aster formation. Aberrant γ-tubulin localization was also observed. These phenotypes suggest that perturbation of spindle microtubules is the primary event leading to the mitotic delays upon FQI1 treatment. Previously, FQIs were shown to specifically inhibit not only LSF DNA-binding activity, which requires LSF oligomerization to tetramers, but also other specific LSF-protein interactions. Other transcription factors participate in mitosis through non-transcriptional means, and we recently reported that LSF directly binds α-tubulin and is present in purified cellular tubulin preparations. Consistent with a microtubule role for LSF, here we show that LSF enhanced the rate of tubulin polymerization in vitro, and FQI1 inhibited such polymerization. To probe whether the FQI1-mediated spindle abnormalities could result from inhibition of mitotic LSF-protein interactions, mass spectrometry was performed using as bait an inducible, tagged form of LSF that is biotinylated by endogenous enzymes. The global proteomics analysis yielded expected associations for a transcription factor, notably with RNA processing machinery, but also to nontranscriptional components. In particular, and consistent with spindle disruption due to FQI treatment, mitotic, FQI1-sensitive interactions were identified between the biotinylated LSF and microtubule-associated proteins that regulate spindle assembly, positioning, and dynamics, as well as centrosome-associated proteins. Probing the mitotic LSF interactome using small molecule inhibitors therefore supported a non-transcriptional role for LSF in mediating progression through mitosis.

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Keefe, Anthony D., Jeremy S. Disch, Jennifer Duffy, Esther C. Lee, Diana Gikunju, Betty Chan, Benjamin D. Levin, et al. "Abstract 5346: Discovery of new targeted protein degraders using DNA-encoded chemistry." Cancer Research 83, no. 7_Supplement (April 4, 2023): 5346. http://dx.doi.org/10.1158/1538-7445.am2023-5346.

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Abstract Bispecific degraders (PROTACs) of ERα are expected to be advantageous over current inhibitors of ERα signaling (aromatase inhibitors/SERMs/SERDs) used to treat ER+ breast cancer. Information from DNA-encoded chemical library screening provides a method to identify novel PROTAC binding features as the linker positioning, and binding elements are determined directly from the screen. After screening ∼120 billion DNA-encoded molecules with ERα WT and 3 gain-of-function mutants, with and without estradiol to identify features that enrich ERα competitively, the off-DNA synthesized small molecule exemplars exhibited nanomolar ERα binding, antagonism, and degradation. Click chemistry synthesis on an alkyne E3 ligase engagers panel and an azide variant that rapidly generated bispecific nanomolar degraders of ERα, with PROTACs inhibiting ER+ MCF7 tumor growth in a mouse xenograft model of breast cancer. This study validates this approach toward identifying novel bispecific degrader leads from DECL screening with minimal optimization. Citation Format: Anthony D. Keefe, Jeremy S. Disch, Jennifer Duffy, Esther C. Lee, Diana Gikunju, Betty Chan, Benjamin D. Levin, Michael I. Monteiro, Sarah A. Talcott, Anthony Lau, Fei Zhou, Anton Kozhushnyan, Neil E. Westlund, Patrick B. Mullins, Yan Yu, Moritz von Rechenberg, Junyi Zhang, Yelena Arnautova, Yanbin Liu, Ying Zhang, Andrew J. McRiner, Anna Kohlmann, Matthew A. Clark, John W. Cuozzo, Christelle Huguet, Shilpi Arora. Discovery of new targeted protein degraders using DNA-encoded chemistry. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5346.

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Ogino, Fedorov, Adams, Okada, Ito, Sugiyama, and Ogino. "Vesiculopolins, a New Class of Anti-Vesiculoviral Compounds, Inhibit Transcription Initiation of Vesiculoviruses." Viruses 11, no. 9 (September 14, 2019): 856. http://dx.doi.org/10.3390/v11090856.

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Vesicular stomatitis virus (VSV) represents a promising platform for developing oncolytic viruses, as well as vaccines against significant human pathogens. To safely control VSV infection in humans, small-molecule drugs that selectively inhibit VSV infection may be needed. Here, using a cell-based high-throughput screening assay followed by an in vitro transcription assay, compounds with a 7-hydroxy-6-methyl-3,4-dihydroquinolin-2(1H)-one structure and an aromatic group at position 4 (named vesiculopolins, VPIs) were identified as VSV RNA polymerase inhibitors. The most effective compound, VPI A, inhibited VSV-induced cytopathic effects and in vitro mRNA synthesis with micromolar to submicromolar 50% inhibitory concentrations. VPI A was found to inhibit terminal de novo initiation rather than elongation for leader RNA synthesis, but not mRNA capping, with the VSV L protein, suggesting that VPI A is targeted to the polymerase domain in the L protein. VPI A inhibited transcription of Chandipura virus, but not of human parainfluenza virus 3, suggesting that it specifically acts on vesiculoviral L proteins. These results suggest that VPIs may serve not only as molecular probes to elucidate the mechanisms of transcription of vesiculoviruses, but also as lead compounds to develop antiviral drugs against vesiculoviruses and other related rhabdoviruses.

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Kelleher, Joseph, Laurent Audoly, Veronica Campbell, Jesse Chen, Nan Ji, Hari Kamadurai, Henry Li, et al. "Targeted Degradation of IRAK4 Protein Via Heterobifunctional Small Molecules for Treatment of MYD88 Mutant Lymphoma." Blood 132, Supplement 1 (November 29, 2018): 2953. http://dx.doi.org/10.1182/blood-2018-99-120148.

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Abstract Recurrent mutations in the scaffolding protein MYD88 are present in 30-40% of activated B cell diffuse lymphocytic B cell lymphoma (ABC-DLBCL)(Ngo et al. Nature 2011). MYD88 links activated interleukin 1 receptor (IL1R) and Toll-like receptors (TLRs) to downstream effectors by nucleating assembly of the Myddosome, a multi-protein complex containing MYD88, the protein kinases IRAK4 and IRAK1 and the pseudokinase IRAK2, via oligomerization of the N-terminal Death Domains in each of these proteins (Motshwene et al. JBC 2009; Lin, Lo and Wu. Nature 2010). The most prevalent MYD88 mutation, L265P, constitutively activates assembly of the Myddosome, causing IRAK4-dependent NFκB and MAP kinase signaling and leading to lymphoma survival and proliferation (Ngo et al. Nature 2011). Constitutive activation of the Myddosome has proven to be difficult to drug. MYD88 and IRAK2 lack enzymatic activity and cannot be targeted by conventional small molecule catalytic inhibitors. There are no IRAK1 inhibitors in clinical trials. Specific inhibitors of the kinase activity of IRAK4 have shown limited activity as single agents in preclinical models of MYD88 mutant lymphoma (Lim et al. Blood 2012; Booher et al. Blood 2014). This is consistent with the observations that there is kinase-independent activity of IRAK4 in mediating downstream signals, such as those leading to induction of NFκB (Qin et al. JBC 2004; Fraczek et al. JBC 2008; Sun et al. Sci Signal. 2016). IRAK4 kinase inhibitors thus might not provide optimal blockade of NFκB-dependent tumor survival signals driven by MYD88 mutations in ABC-DLBCL. Kymera Therapeutics is advancing a new class of drugs based on targeted protein degradation: heterobifunctional molecules that recruit disease-causing proteins to specific E3 ubiquitin ligases, resulting in their ubiquitination and subsequent degradation. We have developed a portfolio of potent and specific degraders of IRAK4 with drug-like properties Our lead molecules cause potent and specific degradation of IRAK4 in the ABC-DLBCL cell lines OCI-LY10 (MYD88 L265P) and U2932 (MYD88 WT) while showing selective cytotoxic effects on OCI-LY10 vs U2932. The apoptotic response is triggered within 24-48 h in OCI-LY10, demonstrated by appearance of cleaved caspase 3 and PARP. Quantitative proteomic studies show selective degradation of IRAK4 vs five to six thousand other proteins detected in OCI-LY10. IRAK4 degraders were tested in an OCI-LY10 xenograft model with daily dosing for 28 days, to determine the level of IRAK4 degradation and impact of that degradation on tumor growth in vivo. We observed that degraders mediated decrease in IRAK4 in vivo and produced a statistically significant decrease in tumor growth rate. Here we will present in vitro and in vivo activity and mechanism of action of our most advanced IRAK4 degraders. These IRAK4 degrader molecules represent a new therapeutic modality and provide an exciting opportunity to treat MYD88 mutation-driven ABC-DLBCL. Disclosures Kelleher: Kymera Therapeutics: Employment, Equity Ownership. Audoly:Kymera Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Campbell:Kymera Therapeutics: Employment, Equity Ownership. Chen:Kymera Therapeutics: Employment, Equity Ownership. Ji:Kymera Therapeutics: Employment, Equity Ownership. Kamadurai:Kymera Therapeutics: Employment, Equity Ownership. Li:Kymera Therapeutics: Employment, Equity Ownership. Loh:Kymera Therapeutics: Employment, Equity Ownership. Rong:Kymera Therapeutics: Employment, Equity Ownership. Vigil:Kymera Therapeutics: Employment, Equity Ownership. Weiss:Kymera Therapeutics: Employment, Equity Ownership. Yuan:Kymera Therapeutics: Employment, Equity Ownership. Zhang:Kymera Therapeutics: Employment, Equity Ownership. Mainolfi:Kymera Therapeutics: Employment, Equity Ownership.

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Da Silva, Gustavo F., Alex Ghetu, Leandro Cerchietti, Jose M. Polo, Andrew Coop, Alexander Mackerell, Gilbert G. Prive, and Ari Melnick. "Design and Development of Small Molecules for Specific Targeted Therapy of Diffuse Large B-Cell Lymphoma." Blood 110, no. 11 (November 16, 2007): 799. http://dx.doi.org/10.1182/blood.v110.11.799.799.

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Abstract BCL6 is the most commonly involved oncogene in diffuse large B-cell lymphoma (DLBCL). BCL6 mediates lymphomagenesis through direct transcriptional repression of target genes including p53 and ATR. BCL6 represses these genes by recruiting three corepressors: SMRT, N-CoR and BCoR. This interaction is mediated by an 18 amino acid corepressor sequence with a unique “lateral groove” motif located in the BCL6 BTB domain. We previously showed that a peptide mimic of the corepressor BCL6-binding sequence could inhibit BCL6 and kill DLBCL cells in vitro and in vivo, without toxicity to normal tissues. Although, transcription factors such as BCL6 that function through protein-protein interactions were traditionally regarded as “undruggable”, we hypothesized that a detailed structural and biochemical analysis might facilitate the design of small molecule inhibitors. Based on our crystal structure of the BCL6-corepressor complex, we used a computational strategy to screen one million small molecules for their ability to potentially dock to a specific lateral groove region. The chemistry of protein contacts in this region led us to predict that small molecules that could dock to this site would have the best chance of destabilizing the BCL6-corepressor complex. Among the top-scoring 100 molecules from this screen, we identified 10 compounds that could specifically inhibit the repressor activity of the BCL6 BTB domain in reporter assays and that displayed direct binding to purified BCL6 BTB domains. Using these leads as molecular scaffolds we generated small libraries of molecules derived from each parental compound. The most active of these families was called “the 57 series”. Series 57 compounds could all specifically block BCL6 repression in reporter assays, and disrupt corepressor/BCL6 complexes at low micromolar concentrations as shown in fluorescence polarization assays. X-ray crystallography of the most active member of the 57 family (called “57-6”) showed that the small molecule docked as predicted in the critical region of the lateral groove. Moreover, 57-6 induced an allosteric conformational change in the entire lateral groove that explains how these small molecules so effectively disrupt the BCL6/corepressor complex. 57-6 was also biologically active, since it could induce expression of BCL6 target genes including p53 and ATR in BCL6-positive DLBCL cells as shown by QPCR. 57-6 had no effect on negative control genes nor in BCL6-negative DLBCL cells. The mechanism of action was confirmed in ChIP assays showed that 57-6 abrogated BCL6 mediated corepressor recruitment to BCL6 target genes but had no effect on negative control genes. Most importantly, 57-6 specifically killed BCL6-positive DLBCL cells but had no effect on BCL6-negative DLBCL cells. A dose escalation experiment in mice revealed no toxic effects. In xenotransplantation experiments, 57-6 potently inhibited the growth of already established human DLBCL tumors in mice, again without toxicity to other organs. In summary, we used a rational approach to design specific and potent small molecule inhibitors of BCL6, which could serve as targeted agents for DLBCL in clinical trials. Our data show that transcription factors are druggable targets that can be harnessed to potentially improve cancer therapy.

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D’Annessa, Ilda, Naama Hurwitz, Valentina Pirota, Giovanni Luca Beretta, Stella Tinelli, Mark Woodford, Mauro Freccero, et al. "Design of Disruptors of the Hsp90–Cdc37 Interface." Molecules 25, no. 2 (January 15, 2020): 360. http://dx.doi.org/10.3390/molecules25020360.

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The molecular chaperone Hsp90 is a ubiquitous ATPase-directed protein responsible for the activation and structural stabilization of a large clientele of proteins. As such, Hsp90 has emerged as a suitable candidate for the treatment of a diverse set of diseases, such as cancer and neurodegeneration. The inhibition of the chaperone through ATP-competitive inhibitors, however, was shown to lead to undesirable side effects. One strategy to alleviate this problem is the development of molecules that are able to disrupt specific protein–protein interactions, thus modulating the activity of Hsp90 only in the particular cellular pathway that needs to be targeted. Here, we exploit novel computational and theoretical approaches to design a set of peptides that are able to bind Hsp90 and compete for its interaction with the co-chaperone Cdc37, which is found to be responsible for the promotion of cancer cell proliferation. In spite of their capability to disrupt the Hsp90–Cdc37 interaction, no important cytotoxicity was observed in human cancer cells exposed to designed compounds. These findings imply the need for further optimization of the compounds, which may lead to new ways of interfering with the Hsp90 mechanisms that are important for tumour growth.

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Pattenden, Samantha G., Jeremy M. Simon, Aminah Wali, Chatura N. Jayakody, Jacob Troutman, Andrew W. McFadden, Joshua Wooten, et al. "High-throughput small molecule screen identifies inhibitors of aberrant chromatin accessibility." Proceedings of the National Academy of Sciences 113, no. 11 (February 29, 2016): 3018–23. http://dx.doi.org/10.1073/pnas.1521827113.

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Mutations in chromatin-modifying proteins and transcription factors are commonly associated with a wide variety of cancers. Through gain- or loss-of-function, these mutations may result in characteristic alterations of accessible chromatin, indicative of shifts in the landscape of regulatory elements genome-wide. The identification of compounds that reverse a specific chromatin signature could lead to chemical probes or potential therapies. To explore whether chromatin accessibility could serve as a platform for small molecule screening, we adapted formaldehyde-assisted isolation of regulatory elements (FAIRE), a chemical method to enrich for nucleosome-depleted genomic regions, as a high-throughput, automated assay. After demonstrating the validity and robustness of this approach, we applied this method to screen an epigenetically targeted small molecule library by evaluating regions of aberrant nucleosome depletion mediated by EWSR1-FLI1, the chimeric transcription factor critical for the bone and soft tissue tumor Ewing sarcoma. As a class, histone deacetylase inhibitors were greatly overrepresented among active compounds. These compounds resulted in diminished accessibility at targeted sites by disrupting transcription of EWSR1-FLI1. Capitalizing on precise differences in chromatin accessibility for drug discovery efforts offers significant advantages because it does not depend on the a priori selection of a single molecular target and may detect novel biologically relevant pathways.

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Ranganathan, Santhalakshmi, Alexander Kornienko, Antonio Evidente, Daniel Romo, and Joseph Taube. "Abstract 6153: Triple negative breast cancer targeted by Ophiobolin A: Epithelial-mesenchymal transition take the lead." Cancer Research 83, no. 7_Supplement (April 4, 2023): 6153. http://dx.doi.org/10.1158/1538-7445.am2023-6153.

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Abstract Triple negative breast cancer (TNBC) has fewer treatment options than other types of invasive breastcancer. Moreover, Epithelial to Mesenchymal Transition (EMT) helps enrichment of cancer stem cells(CSCs) which promotes resistance to chemotherapy. Ophiobolin A (OpA), a drug like small molecule wasrecently found to have anti-CSC properties. Our current study investigated the cell death mechanism(s)induced by OpA in various breast cancer cell lines with respect to epithelial-mesenchymal transition(EMT).The mechanism of cell death elicited by OpA was analyzed by applying inhibitors for specific pathwaysincluding apoptosis, necroptosis and paraptosis and by analyzing markers of cell death using flowcytometry and western blotting. HMLE(R) and HMLE(R)-Twist cell lines were used to assay the role of EMT.The formation of necrosomes was analyzed with exogeneous expression of RIPK3 tagged with greenfluorescence protein (GFP) in HeLa cell line which lacks endogenous RIPK3 expression. The necrosomeformation was identified by formation of puncta using confocal microscopy. Immune compromised SCIDmice were used to analyze the effect of OpA In vivo.The data obtained in the present study indicates that OpA has an increased anticancer effect in TNBCcompared to the estrogen receptor (ER) positive breast cancer cells. Cells having undergone EMT wereshown to have more sensitivity towards OpA when compared to -uninduced cell lines, which is sensitiveto Necrostatin-1, an inhibitor of necroptosis. OpA also diminished the CD44hi/CD24lo population in TNBCcells. However, apoptosis and paraptosis inhibitors failed to rescue cell death which clearly confirms thatOpA induces necroptosis cell death pathway in EMT undergone cells. An increased phosphorylation ofRIPK, a necroptosis protein marker, was observed on OpA treatment compared to the control. OpAtreatment significantly increased puncta TNBC compared to the untreated control cells, furtherconfirming the necroptotic cell death in TNBC. OpA treatment showed a significant tumor regression intumor bearing SCID mice. All together our findings identify that OpA induce necroptosis in EMT-enrichedTNBC. The study further needs an in-depth analysis of involvement of EMT in necroptotic cell death inTNBC.Key words: Triple-negative breast cancer, EMT, Ophiobolin A, Necroptosis, cell deathmechanism Citation Format: Santhalakshmi Ranganathan, Alexander Kornienko, Antonio Evidente, Daniel Romo, Joseph Taube. Triple negative breast cancer targeted by Ophiobolin A: Epithelial-mesenchymal transition take the lead. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6153.

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Kelly, Aileen, Daniel W. Robbins, May Tan, Austin Tenn-McClellan, Joel McIntosh, Jeffrey Wu, Zef Konst, et al. "Targeted Protein Degradation of BTK As a Unique Therapeutic Approach for B Cell Malignancies." Blood 134, Supplement_1 (November 13, 2019): 3805. http://dx.doi.org/10.1182/blood-2019-129262.

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Bruton's tyrosine kinase (BTK) is a key component of B cell receptor signaling and is involved in B cell development and function. BTK plays a crucial role in cell survival in B cell malignancies such as Chronic Lymphocytic Leukemia (CLL), and covalent inhibitors of BTK, such as ibrutinib, have been successful clinically. However, long-term therapy with covalent BTK inhibitors has been shown to generate resistance mutations, which lead to disease progression. New treatments are needed to address this unmet medical need. Small molecule-induced protein degradation offers a unique approach to inhibiting BTK function. Chimeric Targeting Molecules (CTMs) mediate ubiquitylation and proteasomal degradation of specific target proteins. CTMs are comprised of a ubiquitin ligase binding element ("harness"), a chemical linker, and a target binding element ("hook"). Use of CTMs to degrade both WT and ibrutinib-resistant forms of BTK present a novel approach to targeting BTK and could affect both its catalytic and potential scaffolding functions. We have identified multiple CTMs that catalyze BTK degradation in multiple B cell lines; the concentration of one of such CTM, NRX0492, required to degrade 50% BTK (DC50) was < 1 nM after 4 hours. BTK CTMs impair viability in the BTK-dependent ABC-DLBCL cell line, TMD8 (EC50: < 10 nM after 72 hours). These CTMs also induce degradation of the ibrutinib-resistant C481S mutant form of BTK in cells and confer loss of viability in BTKC481S mutant TMD8 cells with EC50 values of < 10 nM compared to > 1 µM for ibrutinib. Oral administration of NRX0492 in mice leads to dose-proportional exposure in plasma and BTK degradation in circulating and splenic B cells: at 6 hours after a single oral dose of NRX0492, 11% BTK remained in mouse splenocytes compared to 100% BTK in mice dosed with vehicle (P < 0.0001). In a WT TMD8 xenograft model, NRX0492 treatment resulted in similar tumor growth inhibition (TGI) as compared to ibrutinib over 23 days of daily oral administration: 54.4% TGI for NRX0492 and 55.8% for Ibrutinib, both as compared to placebo (P = 0.0006 and P = 0.0004, respectively). Notably, in a TMD8 BTKC481S xenograft model, NRX0492 demonstrated superior TGI as compared to ibrutinib: 51.3% versus 15.2%, (P = 0.033). Preclinical safety and toxicity studies for BTK CTMs are ongoing to inform plans for clinical development. CTM-mediated degradation of BTK may provide an alternative therapeutic approach for B cell malignancies, particularly in the ibrutinib-resistant setting. Disclosures Kelly: Nurix Therapeutics: Employment. Robbins:Nurix Therapeutics: Employment. Tan:Nurix Therapeutics: Employment. Tenn-McClellan:Nurix Therapeutics: Employment. McIntosh:Nurix Therapeutics: Employment. Wu:Nurix Therapeutics: Employment. Konst:Nurix Therapeutics: Employment. Kato:Nurix Therapeutics: Employment. Perez:Nurix Therapeutics: Employment. Tung:Nurix Therapeutics: Employment. Kolobova:Nurix Therapeutics: Employment. Ingallinera:Nurix Therapeutics: Employment. McKinnell:Nurix Therapeutics: Employment. Weiss:Nurix Therapeutics: Employment. Noviski:Nurix Therapeutics: Employment. Ye:Nurix Therapeutics: Employment. Peng:Nurix Therapeutics: Employment. Cardozo:Nurix Therapeutics: Employment. Mihalic:Nurix Therapeutics: Employment. Basham:Nurix Therapeutics: Employment. Rountree:Nurix Therapeutics: Employment. Karr:Nurix Therapeutics: Employment. Bence:Nurix Therapeutics: Employment. Zapf:Nurix Therapeutics: Employment. Sands:Nurix Therapeutics: Employment.

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40

Kuroki, K., R. Russnak, and D. Ganem. "Novel N-terminal amino acid sequence required for retention of a hepatitis B virus glycoprotein in the endoplasmic reticulum." Molecular and Cellular Biology 9, no. 10 (October 1989): 4459–66. http://dx.doi.org/10.1128/mcb.9.10.4459-4466.1989.

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The preS1 surface glycoprotein of hepatitis B virus is targeted to the endoplasmic reticulum (ER) and is retained in this organelle when expressed in the absence of other viral gene products. The protein is also acylated at its N terminus with myristic acid. Sequences responsible for its ER retention have been identified through examination of mutants bearing lesions in the preS1 coding region. These studies reveal that such sequences map to the N terminus of the molecule, between residues 6 and 19. Molecules in which this region was present remained in the ER; those in which it had been deleted were secreted from the cell. Although all deletions which allowed efficient secretion also impaired acylation of the polypeptide, myristylation alone was not sufficient for ER retention: point mutations which eliminated myristylation did not lead to secretion. These data indicate that an essential element for ER retention resides in a 14-amino-acid sequence that is unrelated to previously described ER retention signals.

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41

Yosaatmadja, Yuliana, Adam Vorn Patterson, Jeff Bruce Smaill, and Christopher John Squire. "The 1.65 Å resolution structure of the complex of AZD4547 with the kinase domain of FGFR1 displays exquisite molecular recognition." Acta Crystallographica Section D Biological Crystallography 71, no. 3 (February 26, 2015): 525–33. http://dx.doi.org/10.1107/s1399004714027539.

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The fibroblast growth factor receptor (FGFR) family are expressed widely in normal tissues and play a role in tissue repair, inflammation, angiogenesis and development. However, aberrant signalling through this family can lead to cellular proliferation, evasion of apoptosis and induction of angiogenesis, which is implicated in the development of many cancers and also in drug resistance. The high frequency of FGFR amplification or mutation in multiple cancer types is such that this family has been targeted for the discovery of novel, selective drug compounds, with one of the most recently discovered being AZD4547, a subnanomolar (IC50) FGFR1 inhibitor developed by AstraZeneca and currently in clinical trials. The 1.65 Å resolution crystal structure of AZD4547 bound to the kinase domain of FGFR1 has been determined and reveals extensive drug–protein interactions, an integral network of water molecules and the tight closure of the FGFR1 P-loop to form a long, narrow crevice in which the AZD4547 molecule binds.

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42

Kuroki, K., R. Russnak, and D. Ganem. "Novel N-terminal amino acid sequence required for retention of a hepatitis B virus glycoprotein in the endoplasmic reticulum." Molecular and Cellular Biology 9, no. 10 (October 1989): 4459–66. http://dx.doi.org/10.1128/mcb.9.10.4459.

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Анотація:

The preS1 surface glycoprotein of hepatitis B virus is targeted to the endoplasmic reticulum (ER) and is retained in this organelle when expressed in the absence of other viral gene products. The protein is also acylated at its N terminus with myristic acid. Sequences responsible for its ER retention have been identified through examination of mutants bearing lesions in the preS1 coding region. These studies reveal that such sequences map to the N terminus of the molecule, between residues 6 and 19. Molecules in which this region was present remained in the ER; those in which it had been deleted were secreted from the cell. Although all deletions which allowed efficient secretion also impaired acylation of the polypeptide, myristylation alone was not sufficient for ER retention: point mutations which eliminated myristylation did not lead to secretion. These data indicate that an essential element for ER retention resides in a 14-amino-acid sequence that is unrelated to previously described ER retention signals.

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43

Xia, Yuxing, Grace M. Lloyd та Benoit I. Giasson. "Targeted proteolytic products of τ and α-synuclein in neurodegeneration". Essays in Biochemistry 65, № 7 (грудень 2021): 905–12. http://dx.doi.org/10.1042/ebc20210028.

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Abstract CNS pathological inclusions comprising τ or α-synuclein (αSyn) define a spectrum of neurodegenerative diseases, and these can often present concurrently in the same individuals. The aggregation of both proteins is clearly associated with neurodegeneration and the deleterious properties of each protein is further supported by mutations in each gene (MAPT and SNCA, respectively) resulting in disease. The initiating events in most sporadic neurodegenerative diseases are still unclear but growing evidence suggests that the aberrant proteolytic cleavage of τ and αSyn results in products that can be toxic and/or initiate aggregation that can further spread by a prion-like mechanism. The accumulation of some of these cleavage products can further potentiate the progression of protein aggregation transmission and lead to their accumulation in peripheral biofluids such as cerebrospinal fluid (CSF) and blood. The future development of new tools to detect specific τ and αSyn abnormal cleavage products in peripheral biofluids could be useful biomarkers and better understand of the role of unique proteolytic activities could yield therapeutic interventions.

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Franco, Rafael, Vicent Casadó, Antoni Cortés, Carla Ferrada, Josefa Mallol, Amina Woods, Carme Lluis, Enric I. Canela, and Sergi Ferré. "Basic Concepts in G-Protein-Coupled Receptor Homo- and Heterodimerization." Scientific World JOURNAL 7 (2007): 48–57. http://dx.doi.org/10.1100/tsw.2007.197.

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Until recently, heptahelical G-protein-coupled receptors (GPCRs) were considered to be expressed as monomers on the cell surface of neuronal and non-neuronal cells. It is now becoming evident that this view must be overtly changed since these receptors can form homodimers, heterodimers, and higher-order oligomers on the plasma membrane. Here we discuss some of the basics and some new concepts of receptor homo- and heteromerization. Dimers-oligomers modify pharmacology, trafficking, and signaling of receptors. First of all, GPCR dimers must be considered as the main molecules that are targeted by neurotransmitters or by drugs. Thus, binding data must be fitted to dimer-based models. In these models, it is considered that the conformational changes transmitted within the dimer molecule lead to cooperativity. Cooperativity must be taken into account in the binding of agonists-antagonists-drugs and also in the binding of the so-called allosteric modulators. Cooperativity results from the intramolecular cross-talk in the homodimer. As an intramolecular cross-talk in the heterodimer, the binding of one neurotransmitter to one receptor often affects the binding of the second neurotransmitter to the partner receptor. Coactivation of the two receptors in a heterodimer can change completely the signaling pathway triggered by the neurotransmitter as well as the trafficking of the receptors. Heterodimer-specific drugs or dual drugs able to activate the two receptors in the heterodimer simultaneously emerge as novel and promising drugs for a variety of central nervous system (CNS) therapeutic applications.

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Strasser, Jane E., Monica Arribas, Anastasia D. Blagoveshchenskaya, and Daniel F. Cutler. "Secretagogue-triggered Transfer of Membrane Proteins from Neuroendocrine Secretory Granules to Synaptic-like Microvesicles." Molecular Biology of the Cell 10, no. 8 (August 1999): 2619–30. http://dx.doi.org/10.1091/mbc.10.8.2619.

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The membrane proteins of all regulated secretory organelles (RSOs) recycle after exocytosis. However, the recycling of those membrane proteins that are targeted to both dense core granules (DCGs) and synaptic-like microvesicles (SLMVs) has not been addressed. Since neuroendocrine cells contain both RSOs, and the recycling routes that lead to either organelle overlap, transfer between the two pools of membrane proteins could occur during recycling. We have previously demonstrated that a chimeric protein containing the cytosolic and transmembrane domains of P-selectin coupled to horseradish peroxidase is targeted to both the DCG and the SLMV in PC12 cells. Using this chimera, we have characterized secretagogue-induced traffic in PC12 cells. After stimulation, this chimeric protein traffics from DCGs to the cell surface, internalizes into transferrin receptor (TFnR)-positive endosomes and thence to a population of secretagogue-responsive SLMVs. We therefore find a secretagogue-dependent rise in levels of HRP within SLMVs. In addition, the levels within SLMVs of the endogenous membrane protein, synaptotagmin, as well as a green fluorescent protein-tagged version of vesicle-associated membrane protein (VAMP)/synaptobrevin, also show a secretagogue-dependent increase.

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Karwasra, Ritu, Shaban Ahmad, Nagmi Bano, Sahar Qazi, Khalid Raza, Surender Singh, and Saurabh Varma. "Macrophage-Targeted Punicalagin Nanoengineering to Alleviate Methotrexate-Induced Neutropenia: A Molecular Docking, DFT, and MD Simulation Analysis." Molecules 27, no. 18 (September 16, 2022): 6034. http://dx.doi.org/10.3390/molecules27186034.

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Punicalagin is the most bioactive pomegranate polyphenol with high antioxidant and free-radical scavenging activity and can potentially cure different ailments related to the cardiovascular system. The current research work was envisioned to predict the targeting efficiency of punicalagin (PG) nanoparticles to the macrophages, more specifically to bone marrow macrophages. For this, we selected mannose-decorated PLGA-punicalagin nanoparticles (Mn-PLGA-PG), and before formulating this nanocarrier in laboratory settings, we predicted the targeting efficiency of this nanocarrier by in silico analysis. The analysis proceeded with macrophage mannose receptors to be acquainted with the binding affinity and punicalagin-based nanocarrier interactions with this receptor. In silico docking studies of macrophage mannose receptors and punicalagin showed binding interactions on its surface. PG interacted with hydrogen bonds to the charged residue ASP668 and GLY666 and polar residue GLN760 of the Mn receptor. Mannose with a docking score of −5.811 Kcal/mol interacted with four hydrogen bonds and the mannose receptor of macrophage, and in PLGA, it showed a −4.334 Kcal/mol docking score. Further, the analysis proceeded with density functional theory analysis (DFT) and HOMO–LUMO analysis, followed by an extensive 100 ns molecular dynamics simulation to analyse the trajectories showing the slightest deviation and fluctuation. While analysing the ligand and protein interaction, a wonderful interaction was found among the atoms of the ligand and protein residues. This computational study confirms that this nanocarrier could be a promising lead molecule to regulate the incidence of drug-induced neutropenia. Furthermore, experimental validation is required before this can be stated with complete confidence or before human use.

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Rampogu, Shailima, and Mary Rampogu Lemuel. "Network Based Approach in the Establishment of the Relationship between Type 2 Diabetes Mellitus and Its Complications at the Molecular Level Coupled with Molecular Docking Mechanism." BioMed Research International 2016 (2016): 1–6. http://dx.doi.org/10.1155/2016/6068437.

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Diabetes mellitus (DM) is one of the major metabolic disorders that is currently threatening the world. DM is seen associated with obesity and diabetic retinopathy (DR). In the present paper we tried to evaluate the relationship between the three aliments at the gene level and further performed the molecular docking to identify the common drug for all the three diseases. We have adopted several software programs such as Phenopedia, VennViewer, and CDOCKER to accomplish the objective. Our results revealed six genes that commonly associated and are involved in the signalling pathway. Furthermore, evaluation of common gene association from the selected set of genes projected the presence of SIRT1 in all the three aliments. Therefore, we targeted protein 4KXQ which was produced from the gene SIRT1 and challenged it with eight phytochemicals, adopting the CDOCKER. C1 compound has displayed highest -CDOCKER energy and -CDOCKER interaction energy of 43.6905 and 43.3953, respectively. Therefore, this compound is regarded as the most potential lead molecule.

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Zhou, Dan, Yuan Liu, Josephine Ye, Weiwen Ying, Dinesh Chimmanamada, Luisa Shin Ogawa, Takayo Inoue, Patricia Rao, and Yumiko Wada. "Potent anti-inflammatory activity of a novel of class Hsp90 inhibitors for multiple sclerosis (51.1)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 51.1. http://dx.doi.org/10.4049/jimmunol.188.supp.51.1.

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Abstract Current therapies for multiple sclerosis (MS) generally reduce the frequency, severity and duration of relapses, and may slow disease progression, but are not curative. Clinical benefit also comes with side effects that range from mild to life-threatening. Heat shock protein 90 (Hsp90) is a molecular chaperone required for the stability and function of many proteins that modulate cellular response to environmental stresses. Due to its central role in multiple immune-mediated mechanisms, Hsp90 has recently emerged as a potential target for MS therapy. A number of the inflammatory mediators underlying MS are known Hsp90 client proteins, and Hsp90 blockade represents an attractive multi-targeted therapeutic approach given its alternative mechanisms of neuroprotection and inhibition of inflammation. Here we describe a novel class of small molecule inhibitors that preferentially target Hsp90 associated with immune-mediated pathways and which demonstrate potent inhibitory activity, high oral bioavailability and prolonged CNS exposure. Further, the lead compound displays broad activity in a number of relevant in vitro and in vivo models; including inhibition of cytokine production by human PBMCs, decreased nitric oxide production by primary rat astrocytes, and efficacy in an adoptive transfer model of MS. Taken together, this class of Hsp90 inhibitors may potentially provide new avenues to counter immune overstimulation in MS patients.

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Bonami, Rachel, Lindsay Nyhoff, Chrys Hulbert, Jamie Felton, Peggy L. Kendall, and James W. Thomas. "One size doesn’t fit all: SLAM-Associated Protein is dispensable for type 1 diabetes but required for autoantibody-mediated arthritis." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 115.14. http://dx.doi.org/10.4049/jimmunol.202.supp.115.14.

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Abstract Signaling lymphocytic activation molecule-associated protein (SAP), a critical intracellular signaling molecule for T-B interactions, drives Tfh development in germinal centers (GC) in the setting of protective immune responses. SAP promotes long-lived T cell-B cell interactions necessary to sustain germinal center reactions that lead to antibody production. High-affinity islet autoantibodies predict type 1 diabetes (T1D) but do not cause beta cell destruction. This paradox intimates T follicular helper cells (Tfh) as key pathologic effectors. To understand Tfh contribution to autoimmune processes, we investigated the role of SAP in T1D and autoantibody-mediated arthritis. Whereas spontaneous autoimmune arthritis depended on SAP, organized insulitis and diabetes onset were unabated, despite a blocked anti-insulin vaccine response. SAP-deficient T cell function was therefore investigated in the non-obese diabetic (NOD) T1D model. B lymphocyte antigen presentation drove SAP-deficient NOD T cell proliferation. Although germinal center B cell formation was markedly reduced, GC-Tfh were found at sites of autoimmune attack in SAP-deficient NOD mice. Thus, Tfh induced in germinal center reactions are dispensable for T1D and suggest that the autoimmune process in NOD retains pathogenic Tfh in the absence of prolonged B cell interactions. These findings demonstrate that SAP is essential for Tfh formation and autoimmunity when autoantibodies play a central role in autoimmune arthritis but not in cell-mediated T1D. SAP inhibition is thus a compelling strategy for autoantibody-mediated disease treatment, but additional cognate cellular interaction molecules must be targeted to treat cell-mediated autoimmune diseases.

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Zuo, Jun, Steve Kye, Kevin K. Quinn, Paige Cooper, Robert Damoiseaux, and Paul Krogstad. "Discovery of Structurally Diverse Small-Molecule Compounds with Broad Antiviral Activity against Enteroviruses." Antimicrobial Agents and Chemotherapy 60, no. 3 (December 28, 2015): 1615–26. http://dx.doi.org/10.1128/aac.02646-15.

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Antiviral drugs do not currently exist for the treatment of enterovirus infections, which are often severe and potentially life-threatening. We conducted high-throughput molecular screening and identified a structurally diverse set of compounds that inhibit the replication of coxsackievirus B3, a commonly encountered enterovirus. These compounds did not interfere with the function of the viral internal ribosome entry site or with the activity of the viral proteases, but they did drastically reduce the synthesis of viral RNA and viral proteins in infected cells. Sequence analysis of compound-resistant mutants suggests that the viral 2C protein is targeted by most of these compounds. These compounds demonstrated antiviral activity against a panel of the most commonly encountered enteroviruses and thus represent potential leads for the development of broad-spectrum anti-enteroviral drugs.

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