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Binding to an Unusual Inactive Kinase Conformation by Highly Selective Inhibitors of Inositol-Requiring Enzyme 1? Kinase-Endoribonuclease.


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 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.

SUBMITTER: Colombano G 

PROVIDER: S-EPMC6437697 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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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 i  ...[more]

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