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

Xie, Yiyue; TUMMALA, PADMAJA; Oakley, Aaron; Deora, Girdhar Singh; Nakano, Yuji; Rooke, Melissa; Cuellar, Matthew; Strasser, Jessica; Dahlin, Jayme L; Walters, Michael A; Casarotto, Marco; Board, Philip; Baell, Jonathan B

Description

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...[Show more]

dc.contributor.authorXie, Yiyue
dc.contributor.authorTUMMALA, PADMAJA
dc.contributor.authorOakley, Aaron
dc.contributor.authorDeora, Girdhar Singh
dc.contributor.authorNakano, Yuji
dc.contributor.authorRooke, Melissa
dc.contributor.authorCuellar, Matthew
dc.contributor.authorStrasser, Jessica
dc.contributor.authorDahlin, Jayme L
dc.contributor.authorWalters, Michael A
dc.contributor.authorCasarotto, Marco
dc.contributor.authorBoard, Philip
dc.contributor.authorBaell, Jonathan B
dc.date.accessioned2021-01-11T05:06:06Z
dc.identifier.issn0022-2623
dc.identifier.urihttp://hdl.handle.net/1885/219280
dc.description.abstractGlutathione 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.
dc.description.sponsorshipAcknowledged 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.
dc.format.mimetypeapplication/pdf
dc.language.isoen_AU
dc.publisherAmerican Chemical Society
dc.rights© 2020 American Chemical Society
dc.sourceJournal of Medicinal Chemistry
dc.titleDevelopment of Benzenesulfonamide Derivatives as Potent Glutathione Transferase Omega-1 Inhibitors
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume63
dc.date.issued2020
local.identifier.absfor060199 - Biochemistry and Cell Biology not elsewhere classified
local.identifier.ariespublicationa383154xPUB11196
local.publisher.urlhttps://dx.doi.org/10.1021/acs.jmedchem.9b01391?ref=pdf
local.type.statusPublished Version
local.contributor.affiliationXie, Yiyue, Monash University
local.contributor.affiliationTummala, Padmaja, College of Health and Medicine, ANU
local.contributor.affiliationOakley, Aaron, University of Wollongong
local.contributor.affiliationDeora, Girdhar Singh, Monash University
local.contributor.affiliationNakano, Yuji, Monash University
local.contributor.affiliationRooke, Melissa, College of Health and Medicine, ANU
local.contributor.affiliationCuellar, Matthew, University of Minnesota
local.contributor.affiliationStrasser, Jessica, University of Minnesota
local.contributor.affiliationDahlin, Jayme L, Brigham and Women’s Hospital
local.contributor.affiliationWalters, Michael A, University of Minnesota
local.contributor.affiliationCasarotto, Marco, College of Health and Medicine, ANU
local.contributor.affiliationBoard, Philip, College of Health and Medicine, ANU
local.contributor.affiliationBaell, Jonathan B, Monash University
local.description.embargo2099-12-31
dc.relationhttp://purl.org/au-research/grants/nhmrc/APP1124673
local.bibliographicCitation.issue6
local.bibliographicCitation.startpage2894
local.bibliographicCitation.lastpage2914
local.identifier.doi/10.1021/acs.jmedchem.9b01391
local.identifier.absseo920102 - Cancer and Related Disorders
dc.date.updated2020-11-02T04:17:04Z
dc.provenancehttps://v2.sherpa.ac.uk/id/publication/7786
CollectionsANU Research Publications

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