dc.contributor.author | Colombano, G | |
dc.contributor.author | Caldwell, JJ | |
dc.contributor.author | Matthews, TP | |
dc.contributor.author | Bhatia, C | |
dc.contributor.author | Joshi, A | |
dc.contributor.author | McHardy, T | |
dc.contributor.author | Mok, NY | |
dc.contributor.author | Newbatt, Y | |
dc.contributor.author | Pickard, L | |
dc.contributor.author | Strover, J | |
dc.contributor.author | Hedayat, S | |
dc.contributor.author | Walton, MI | |
dc.contributor.author | Myers, SM | |
dc.contributor.author | Jones, AM | |
dc.contributor.author | Saville, H | |
dc.contributor.author | McAndrew, C | |
dc.contributor.author | Burke, R | |
dc.contributor.author | Eccles, SA | |
dc.contributor.author | Davies, FE | |
dc.contributor.author | Bayliss, R | |
dc.contributor.author | Collins, I | |
dc.date.accessioned | 2019-03-04T14:35:08Z | |
dc.date.issued | 2019-02-19 | |
dc.identifier.citation | Journal of medicinal chemistry, 2019, 62 (5), pp. 2447 - 2465 | |
dc.identifier.issn | 0022-2623 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3112 | |
dc.identifier.eissn | 1520-4804 | |
dc.identifier.doi | 10.1021/acs.jmedchem.8b01721 | |
dc.description.abstract | A 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. | |
dc.format | Print-Electronic | |
dc.format.extent | 2447 - 2465 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER CHEMICAL SOC | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Humans | |
dc.subject | Biopolymers | |
dc.subject | Endoribonucleases | |
dc.subject | Protein-Serine-Threonine Kinases | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Crystallography, X-Ray | |
dc.subject | Allosteric Regulation | |
dc.subject | Protein Conformation | |
dc.subject | Dimerization | |
dc.subject | Phosphorylation | |
dc.subject | HEK293 Cells | |
dc.subject | Endoplasmic Reticulum Stress | |
dc.title | Binding to an Unusual Inactive Kinase Conformation by Highly Selective Inhibitors of Inositol-Requiring Enzyme 1α Kinase-Endoribonuclease. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2019-02-19 | |
rioxxterms.versionofrecord | 10.1021/acs.jmedchem.8b01721 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2019-03-05 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Journal of medicinal chemistry | |
pubs.issue | 5 | |
pubs.notes | Not known | |
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/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Functional Genomics | |
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/Functional 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.organisational-group | /ICR/Students | |
pubs.organisational-group | /ICR/Students/PhD and MPhil | |
pubs.organisational-group | /ICR/Students/PhD and MPhil/16/17 Starting Cohort | |
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/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Functional Genomics | |
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/Functional 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.organisational-group | /ICR/Students | |
pubs.organisational-group | /ICR/Students/PhD and MPhil | |
pubs.organisational-group | /ICR/Students/PhD and MPhil/16/17 Starting Cohort | |
pubs.publication-status | Published | |
pubs.volume | 62 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Medicinal Chemistry 2 | |
icr.researchteam | Functional Genomics | |
icr.researchteam | Hit Discovery & Structural Design | |
dc.contributor.icrauthor | Caldwell, John | |
dc.contributor.icrauthor | Matthews, Thomas | |
dc.contributor.icrauthor | McHardy, Tatiana | |
dc.contributor.icrauthor | Hedayat-Husseyin, Somaieh | |
dc.contributor.icrauthor | Burke, Rosemary | |
dc.contributor.icrauthor | Collins, Ian | |