Development of Benzenesulfonamide Derivatives as Potent Glutathione Transferase Omega-1 Inhibitors
| العنوان: | Development of Benzenesulfonamide Derivatives as Potent Glutathione Transferase Omega-1 Inhibitors |
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| المؤلفون: | Girdhar Singh Deora, Aaron J. Oakley, Philip G. Board, Yuji Nakano, Jayme L. Dahlin, Padmaja Tummala, Jonathan B. Baell, Jessica M. Strasser, Yiyue Xie, Michael A. Walters, Melissa Rooke, Matthew E. Cuellar, Marco G. Casarotto |
| المصدر: | Journal of Medicinal Chemistry. 63:2894-2914 |
| بيانات النشر: | American Chemical Society (ACS), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Male, Cell, 01 natural sciences, law.invention, Mice, Structure-Activity Relationship, 03 medical and health sciences, Drug Development, law, Drug Discovery, medicine, Animals, Humans, Structure–activity relationship, Enzyme Inhibitors, Glutathione Transferase, 030304 developmental biology, chemistry.chemical_classification, Sulfonamides, 0303 health sciences, Assay, Interleukin, 0104 chemical sciences, Molecular Docking Simulation, 010404 medicinal & biomolecular chemistry, Enzyme, medicine.anatomical_structure, chemistry, Biochemistry, Drug development, Recombinant DNA, Molecular Medicine, Cysteine |
| الوصف: | Glutathione transferase omega-1 (GSTO1-1) is an enzyme whose function supports the activation of interleukin (IL)-1β and IL-18 that are implicated in a variety of inflammatory disease states for which small-molecule inhibitors are sought. The potent reactivity of the active-site cysteine has resulted in reported inhibitors that act by covalent labeling. In this study, structure-activity relationship (SAR) elaboration of the reported GSTO1-1 inhibitor C1-27 was undertaken. Compounds were evaluated for inhibitory activity toward purified recombinant GSTO1-1 and for indicators of target engagement in cell-based assays. As covalent inhibitors, the kinact/KI values of selected compounds were determined, as well as in vivo pharmacokinetics analysis. Cocrystal structures of key novel compounds in complex with GSTO1-1 were also solved. This study represents the first application of a biochemical assay for GSTO1-1 to determine kinact/KI values for tested inhibitors and the most extensive set of cell-based data for a GSTO1-1 inhibitor SAR series reported to date. Our research culminated in the discovery of 25, which we propose as the preferred biochemical tool to interrogate cellular responses to GSTO1-1 inhibition. |
| تدمد: | 1520-4804 0022-2623 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d9d34d91fc9b9fcdcb3312475033c026 https://doi.org/10.1021/acs.jmedchem.9b01391 |
| حقوق: | CLOSED |
| رقم الأكسشن: | edsair.doi.dedup.....d9d34d91fc9b9fcdcb3312475033c026 |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 15204804 00222623 |
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