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dc.contributor.authorColombano, Gen_US
dc.contributor.authorCaldwell, JJen_US
dc.contributor.authorMatthews, TPen_US
dc.contributor.authorBhatia, Cen_US
dc.contributor.authorJoshi, Aen_US
dc.contributor.authorMcHardy, Ten_US
dc.contributor.authorMok, NYen_US
dc.contributor.authorNewbatt, Yen_US
dc.contributor.authorPickard, Len_US
dc.contributor.authorStrover, Jen_US
dc.contributor.authorHedayat, Sen_US
dc.contributor.authorWalton, MIen_US
dc.contributor.authorMyers, SMen_US
dc.contributor.authorJones, AMen_US
dc.contributor.authorSaville, Hen_US
dc.contributor.authorMcAndrew, Cen_US
dc.contributor.authorBurke, Ren_US
dc.contributor.authorEccles, SAen_US
dc.contributor.authorDavies, FEen_US
dc.contributor.authorBayliss, Ren_US
dc.contributor.authorCollins, Ien_US
dc.coverage.spatialUnited Statesen_US
dc.date.accessioned2019-03-04T14:35:08Z
dc.date.issued2019-03-14en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/30779566en_US
dc.identifier.citationJ Med Chem, 2019, 62 (5), pp. 2447 - 2465en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3112
dc.identifier.eissn1520-4804en_US
dc.identifier.doi10.1021/acs.jmedchem.8b01721en_US
dc.description.abstractA series of imidazo[1,2- b]pyridazin-8-amine kinase inhibitors were discovered to allosterically inhibit the endoribonuclease function of the dual kinase-endoribonuclease inositol-requiring enzyme 1α (IRE1α), a key component of the unfolded protein response in mammalian cells and a potential drug target in multiple human diseases. Inhibitor optimization gave compounds with high kinome selectivity that prevented endoplasmic reticulum stress-induced IRE1α oligomerization and phosphorylation, and inhibited endoribonuclease activity in human cells. X-ray crystallography showed the inhibitors to bind to a previously unreported and unusually disordered conformation of the IRE1α kinase domain that would be incompatible with back-to-back dimerization of the IRE1α protein and activation of the endoribonuclease function. These findings increase the repertoire of known IRE1α protein conformations and can guide the discovery of highly selective ligands for the IRE1α kinase site that allosterically inhibit the endoribonuclease.en_US
dc.format.extent2447 - 2465en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.titleBinding to an Unusual Inactive Kinase Conformation by Highly Selective Inhibitors of Inositol-Requiring Enzyme 1α Kinase-Endoribonuclease.en_US
dc.typeJournal Article
dcterms.dateAccepted2019-02-19en_US
rioxxterms.versionofrecord10.1021/acs.jmedchem.8b01721en_US
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0en_US
rioxxterms.licenseref.startdate2019-03-14en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfJ Med Chemen_US
pubs.issue5en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Hit Discovery & Structural Design
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 2
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gastrointestinal Cancer Biology and Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Hit Discovery & Structural Design
pubs.publication-statusPublisheden_US
pubs.volume62en_US
pubs.embargo.termsNot knownen_US
icr.researchteamMedicinal Chemistry 2en_US
icr.researchteamGastrointestinal Cancer Biology and Genomicsen_US
icr.researchteamHit Discovery & Structural Designen_US
dc.contributor.icrauthorCollins, Ianen_US
dc.contributor.icrauthorCaldwell, Johnen_US
dc.contributor.icrauthorMatthews, Thomasen_US
dc.contributor.icrauthorHedayat, Somaiehen_US
dc.contributor.icrauthorBurke, Rosemaryen_US
dc.contributor.icrauthorMcHardy, Tatianaen_US


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