6pno
From Proteopedia
Human GSTO1-1 complexed with 2-chloro-N-(4-chloro-3-(N-isopropylsulfamoyl)phenyl)acetamide
Structural highlights
FunctionGSTO1_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 PubMedGlutathione 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. See AlsoReferences
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