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

• Published in: Journal of medicinal chemistry Vol. 63; no. 6; pp. 2894 - 2914
• Main Authors: Xie, Yiyue, Tummala, Padmaja, Oakley, Aaron J, Deora, Girdhar Singh, Nakano, Yuji, Rooke, Melissa, Cuellar, Matthew E, Strasser, Jessica M, Dahlin, Jayme L, Walters, Michael A, Casarotto, Marco G, Board, Philip G, Baell, Jonathan B
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.03.2020; Amer Chemical Soc
• Subjects: Animals; Benzenesulfonamides; Chemistry, Medicinal; Drug Development; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Glutathione Transferase - antagonists & inhibitors; Glutathione Transferase - chemistry; Glutathione Transferase - metabolism; Humans; Life Sciences & Biomedicine; Male; Mice; Molecular Docking Simulation; Pharmacology & Pharmacy; Science & Technology; Structure-Activity Relationship; Sulfonamides - chemistry; Sulfonamides - pharmacology; IN-VITRO; COVALENT; RESISTANCE; REACTIVITY; ARYL; ASSAY INTERFERENCE; PROTEOMIC ANALYSIS; IDENTIFICATION; CANCER; GSTO1-1
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.9b01391

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 k inact/K I 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 k inact/K I 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.