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

Date

2020

Authors

Xie, Yiyue
TUMMALA, PADMAJA
Oakley, Aaron
Deora, Girdhar Singh
Nakano, Yuji
Rooke, Melissa
Cuellar, Matthew
Strasser, Jessica
Dahlin, Jayme L
Walters, Michael A

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Volume Title

Publisher

American Chemical Society

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 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.

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Citation

Source

Journal of Medicinal Chemistry

Type

Journal article

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Restricted until

2099-12-31