| Structural highlights
Function
[GSTO1_HUMAN] Exhibits glutathione-dependent thiol transferase and dehydroascorbate reductase activities. Has S-(phenacyl)glutathione reductase activity. Has also glutathione S-transferase activity. Participates in the biotransformation of inorganic arsenic and reduces monomethylarsonic acid (MMA) and dimethylarsonic acid.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
Glutathione transferase omega-1 (GSTO1-1) is an enzyme whose function supports the activation of IL-1beta 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 labelling. In this study, SAR elaboration of the reported GSTO1-1 inhibitor C1-27 was undertaken. Compounds were evaluated for inhibitory activity towards 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. Co-crystal 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 23, which we propose as the preferred biochemical tool to interrogate cellular responses to GSTO1-1 inhibition.
Development of Benzenesulfonamide Derivatives as Potent Glutathione Transferase Omega-1 Inhibitors.,Xie Y, Tummala P, Oakley AJ, Deora GS, Nakano Y, Rooke M, Cuellar M, Strasser J, Dahlin JL, Walters MA, Casarotto MG, Board PG, Baell JB J Med Chem. 2020 Feb 27. doi: 10.1021/acs.jmedchem.9b01391. PMID:32105470[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Board PG, Coggan M, Chelvanayagam G, Easteal S, Jermiin LS, Schulte GK, Danley DE, Hoth LR, Griffor MC, Kamath AV, Rosner MH, Chrunyk BA, Perregaux DE, Gabel CA, Geoghegan KF, Pandit J. Identification, characterization, and crystal structure of the Omega class glutathione transferases. J Biol Chem. 2000 Aug 11;275(32):24798-806. PMID:10783391 doi:10.1074/jbc.M001706200
- ↑ Zakharyan RA, Sampayo-Reyes A, Healy SM, Tsaprailis G, Board PG, Liebler DC, Aposhian HV. Human monomethylarsonic acid (MMA(V)) reductase is a member of the glutathione-S-transferase superfamily. Chem Res Toxicol. 2001 Aug;14(8):1051-7. PMID:11511179
- ↑ Board PG, Anders MW. Glutathione transferase omega 1 catalyzes the reduction of S-(phenacyl)glutathiones to acetophenones. Chem Res Toxicol. 2007 Jan;20(1):149-54. PMID:17226937 doi:10.1021/tx600305y
- ↑ Board PG, Coggan M, Cappello J, Zhou H, Oakley AJ, Anders MW. S-(4-Nitrophenacyl)glutathione is a specific substrate for glutathione transferase omega 1-1. Anal Biochem. 2008 Mar 1;374(1):25-30. Epub 2007 Sep 29. PMID:18028863 doi:10.1016/j.ab.2007.09.029
- ↑ Zhou H, Brock J, Casarotto MG, Oakley AJ, Board PG. Novel folding and stability defects cause a deficiency of human glutathione transferase omega 1. J Biol Chem. 2011 Feb 11;286(6):4271-9. Epub 2010 Nov 24. PMID:21106529 doi:10.1074/jbc.M110.197822
- ↑ Xie Y, Tummala P, Oakley AJ, Deora GS, Nakano Y, Rooke M, Cuellar M, Strasser J, Dahlin JL, Walters MA, Casarotto MG, Board PG, Baell JB. Development of Benzenesulfonamide Derivatives as Potent Glutathione Transferase Omega-1 Inhibitors. J Med Chem. 2020 Feb 27. doi: 10.1021/acs.jmedchem.9b01391. PMID:32105470 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b01391
|
