2. Academic Validation
  3. Binding to an Unusual Inactive Kinase Conformation by Highly Selective Inhibitors of Inositol-Requiring Enzyme 1α Kinase-Endoribonuclease

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

  • J Med Chem. 2019 Mar 14;62(5):2447-2465. doi: 10.1021/acs.jmedchem.8b01721.
Giampiero Colombano,  John J Caldwell,  Thomas P Matthews,  Chitra Bhatia 1,  Amar Joshi 1,  Tatiana McHardy,  Ngai Yi Mok,  Yvette Newbatt,  Lisa Pickard,  Jade Strover,  Somaieh Hedayat,  Michael I Walton,  Stephanie M Myers,  Alan M Jones,  Harry Saville,  Craig McAndrew,  Rosemary Burke,  Suzanne A Eccles,  Faith E Davies,  Richard Bayliss 1 2,  Ian Collins
Affiliations

Affiliations

  • 1 Department of Molecular and Cell Biology , University of Leicester , Leicester LE1 7RH , U.K.
  • 2 School of Molecular and Cellular Biology, Faculty of Biological Sciences , University of Leeds , Leeds LS2 9JT , U.K.
PMID: 30779566 DOI: 10.1021/acs.jmedchem.8b01721
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.

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