6PNO

Human GSTO1-1 complexed with 2-chloro-N-(4-chloro-3-(N-isopropylsulfamoyl)phenyl)acetamide

6PNO の概要

• エントリーDOI: 10.2210/pdb6pno/pdb
• 分子名称: Glutathione S-transferase omega-1, 2-chloro-N-{4-chloro-3-[(propan-2-yl)sulfamoyl]phenyl}acetamide, L(+)-TARTARIC ACID, ... (5 entities in total)
• 機能のキーワード: glutathione transferase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 28232.13

構造登録者

Oakley, A.J. (登録日: 2019-07-02, 公開日: 2019-07-24, 最終更新日: 2024-11-20)

主引用文献

Xie, Y.,Tummala, P.,Oakley, A.J.,Deora, G.S.,Nakano, Y.,Rooke, M.,Cuellar, M.E.,Strasser, J.M.,Dahlin, J.L.,Walters, M.A.,Casarotto, M.G.,Board, P.G.,Baell, J.B.
Development of Benzenesulfonamide Derivatives as Potent Glutathione Transferase Omega-1 Inhibitors.
J.Med.Chem., 63:2894-2914, 2020

PubMed Abstract: 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 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 / 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 / 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 , which we propose as the preferred biochemical tool to interrogate cellular responses to GSTO1-1 inhibition.

PubMed: 32105470
DOI: 10.1021/acs.jmedchem.9b01391

実験手法

X-RAY DIFFRACTION (1.82 Å)