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

Yiyue 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

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2894-2914
Number of pages21
JournalJournal of medicinal chemistry
Volume63
Issue number6
DOIs
StatePublished - Mar 26 2020

Bibliographical note

Funding Information:
The Centre for Drug Candidate Optimization (CDCO) of the Monash Institute of Pharmaceutical Sciences (MIPS) is gratefully acknowledged for testing the kinetic solubility and the metabolic stability of C1-27 and the mice PK of C1-27 , 3d , 22e , and 25 . This work was supported by Project Grant APP1124673 from the National Health and Medical Research Council of Australia (NHMRC) to Philip G. Board, Marco G. Casarotto, and Aaron J. Oakley and by Project Grant APP1156455 from the NHMRC to Jonathan B. Baell, Philip G. Board, Aaron J. Oakley, and Marco G. Casarotto. The NHMRC is also thanked for Fellowship support for Jonathan B. Baell (2012-2016 Senior Research Fellowship No. 1020411, 2017−present Principal Research Fellowship No. 1117602). Acknowledged is the Australian Federal Government Education Investment Fund Super Science Initiative and the Victorian State Government, Victoria Science Agenda Investment Fund for infrastructure support and the facilities, and the scientific and technical assistance of the Australian Translational Medicinal Chemistry Facility (ATMCF), MIPS. ATMCF is supported by Therapeutic Innovation Australia (TIA). TIA is supported by the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program.

Publisher Copyright:
© 2020 American Chemical Society.

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