Colombano, G, Caldwell, JJ, Matthews, TP et al. (18 more authors) (2019) Binding to an unusual inactive kinase conformation by highly selective inhibitors of inositol-requiring enzyme 1a kinase-endoribonuclease. Journal of Medicinal Chemistry, 62 (5). pp. 2447-2465. ISSN 0022-2623
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2019 American Chemical Society. This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) |
Funding Information: | Funder Grant number Cancer Research UK C24461/A12772 |
Depositing User: | Symplectic Publications |
Date Deposited: | 01 Mar 2019 17:12 |
Last Modified: | 19 Feb 2020 01:38 |
Status: | Published |
Publisher: | American Chemical Society |
Identification Number: | 10.1021/acs.jmedchem.8b01721 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:142967 |