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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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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Journal of Medicinal Chemistry
Type
Journal article
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Restricted until
2099-12-31
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