Binding to an unusual inactive kinase conformation by highly selective inhibitors of inositol-requiring enzyme 1α kinase-endoribonuclease

Colombano, Giampiero, Caldwell, John J, Matthews, Thomas Peter, Bhatia, Chitra, Joshi, Amar, McHardy, Tatiana, Mok, Ngai Yi, Newbatt, Yvette, Pickard, Lisa, Strover, Jade, Hedayat, Somaieh, Walton, Michael Ian, Myers, Stephanie, Jones, Alan Morenc, Saville, Harry, McAndrew, Craig, Burke, Rosemary, Eccles, Suzanne, Davies, Faith, Bayliss, Richard and Collins, Ian (2019) Binding to an unusual inactive kinase conformation by highly selective inhibitors of inositol-requiring enzyme 1α kinase-endoribonuclease. Journal of Medicinal Chemistry, 62 (5). pp. 2447-2465. ISSN 0022-2623

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Abstract

A series of imidazo[1,2-b]pyridazin-8-amine kinase inhibitors was discovered to allosterically inhibit the endoribonuclease function of the dual kinase-endoribonuclease inositol-requiring enzyme 1 (IRE1, 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 IRE1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 IRE1 kinase domain that would be incompatible with back-to-back dimerization of the IRE1 protein and activation of the endoribonuclease function. These findings increase the repertoire of known IRE1 protein conformations and can guide the discovery of highly selective ligands for the IRE1 kinase site that allosterically inhibit the endoribonuclease.

Item Type: Article
Subjects: Sciences > Chemistry
Divisions: Faculty of Health Sciences and Wellbeing
Faculty of Health Sciences and Wellbeing > School of Pharmacy and Pharmaceutical Sciences
Depositing User: Stephanie Myers
Date Deposited: 25 Mar 2019 16:16
Last Modified: 26 Feb 2020 14:24
URI: http://sure.sunderland.ac.uk/id/eprint/10405

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