70325-46-1Relevant articles and documents
Development of Benzenesulfonamide Derivatives as Potent Glutathione Transferase Omega-1 Inhibitors
Xie, Yiyue,Tummala, Padmaja,Oakley, Aaron J.,Deora, Girdhar Singh,Nakano, Yuji,Rooke, Melissa,Cuellar, Matthew E.,Strasser, Jessica M.,Dahlin, Jayme L.,Walters, Michael A.,Casarotto, Marco G.,Board, Philip G.,Baell, Jonathan B.
, p. 2894 - 2914 (2020/04/08)
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.
