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 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.