posted on 2020-03-16, 15:29authored byYiyue Xie, Padmaja Tummala, Aaron J. Oakley, Girdhar Singh Deora, Yuji Nakano, Melissa Rooke, Matthew E. Cuellar, Jessica M. Strasser, Jayme L. Dahlin, Michael A. Walters, Marco G. Casarotto, Philip G. Board, Jonathan B. Baell
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.