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

Journal Article


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.

Publication Date


  • 2020

Citation


  • Xie, Y., Tummala, P., Oakley, A. J., Deora, G. S., Nakano, Y., Rooke, M., . . . Baell, J. B. (2020). Development of Benzenesulfonamide Derivatives as Potent Glutathione Transferase Omega-1 Inhibitors. Journal of Medicinal Chemistry, 63(6), 2894-2914. doi:10.1021/acs.jmedchem.9b01391

Scopus Eid


  • 2-s2.0-85082542472

Web Of Science Accession Number


Start Page


  • 2894

End Page


  • 2914

Volume


  • 63

Issue


  • 6

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.

Publication Date


  • 2020

Citation


  • Xie, Y., Tummala, P., Oakley, A. J., Deora, G. S., Nakano, Y., Rooke, M., . . . Baell, J. B. (2020). Development of Benzenesulfonamide Derivatives as Potent Glutathione Transferase Omega-1 Inhibitors. Journal of Medicinal Chemistry, 63(6), 2894-2914. doi:10.1021/acs.jmedchem.9b01391

Scopus Eid


  • 2-s2.0-85082542472

Web Of Science Accession Number


Start Page


  • 2894

End Page


  • 2914

Volume


  • 63

Issue


  • 6