Development of Benzenesulfonamide Derivatives as Potent Glutathione Transferase Omega‑1 Inhibitors

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 resulte...

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Veröffentlicht in:Journal of medicinal chemistry 2020-03, Vol.63 (6), p.2894-2914
Hauptverfasser: 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
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Sprache:eng
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Zusammenfassung: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 k inact/K I 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 k inact/K I 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.9b01391