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

Research output: Contribution to journalArticlepeer-review


  • Giampiero Colombano
  • John J. Caldwell
  • Thomas P. Matthews
  • Chitra Bhatia
  • Amar Joshi
  • Tatiana McHardy
  • Ngai Yi Mok
  • Yvette Newbatt
  • Lisa Pickard
  • Jade Strover
  • Somaieh Hedayat
  • Michael I. Walton
  • Stephanie M. Myers
  • Harry Saville
  • Craig McAndrew
  • Rosemary Burke
  • Suzanne A. Eccles
  • Faith E. Davies
  • Richard Bayliss
  • Ian Collins

Colleges, School and Institutes


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.


Original languageEnglish
Pages (from-to)2447-2465
Number of pages19
JournalJournal of Medicinal Chemistry
Issue number5
Early online date19 Feb 2019
Publication statusPublished - 1 Mar 2019

ASJC Scopus subject areas

Sustainable Development Goals