Binding to an Unusual Inactive Kinase Conformation by Highly Selective Inhibitors of Inositol-Requiring Enzyme 1α Kinase-Endoribonuclease.
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Date
2019-02-19ICR Author
Author
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, SM
Jones, AM
Saville, H
McAndrew, C
Burke, R
Eccles, SA
Davies, FE
Bayliss, R
Collins, I
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Subject
Humans
Biopolymers
Endoribonucleases
Protein-Serine-Threonine Kinases
Protein Kinase Inhibitors
Crystallography, X-Ray
Allosteric Regulation
Protein Conformation
Dimerization
Phosphorylation
HEK293 Cells
Endoplasmic Reticulum Stress
Research team
Medicinal Chemistry 2
Functional Genomics
Hit Discovery & Structural Design
Language
eng
Date accepted
2019-02-19
License start date
2019-03-05
Citation
Journal of medicinal chemistry, 2019, 62 (5), pp. 2447 - 2465
Publisher
AMER CHEMICAL SOC