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Publication Abstract from PubMed

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 1alpha (IRE1alpha), 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 IRE1alpha 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 IRE1alpha kinase domain that would be incompatible with back-to-back dimerization of the IRE1alpha protein and activation of the endoribonuclease function. These findings increase the repertoire of known IRE1alpha protein conformations and can guide the discovery of highly selective ligands for the IRE1alpha kinase site that allosterically inhibit the endoribonuclease.

Binding to an unusual inactive kinase conformation by highly selective inhibitors of inositol-requiring enzyme 1alpha kinase-endoribonuclease.,Colombano G, Caldwell JJ, Matthews TP, Bhatia C, Joshi A, McHardy T, Mok NY, Newbatt Y, Pickard L, Strover J, Hedayat S, Walton MI, Myers S, Jones AM, Saville H, McAndrew C, Burke R, Eccles S, Davies F, Bayliss R, Collins I J Med Chem. 2019 Feb 19. doi: 10.1021/acs.jmedchem.8b01721. PMID:30779566^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.