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

Imidazopyridazine Acetylcholinesterase Inhibitors Display Potent Anti-Proliferative Effects in the Human Neuroblastoma Cell-Line, IMR-32

“…Various other substitutions on the imidazo[1,2- b ]pyridazine skeleton have also resulted in compounds that showed inhibition of cell proliferation, although the targets of action were different. These include the mitotic protein, haspin [ 69 ], interleukin-1 receptor-associated kinase 4 [ 70 ], inositol-requiring enzyme 1α kinase [ 71 ], dihydrofolate reductase [ 72 ], and MAPK-interacting kinase (MNK) [ 73 ]. However, the effect of these various substituent imidazo[1,2- b ]pyridazine compounds on AChE activity has not been reported.…”

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

“…44,45 Kinase site inhibitors that can simultaneously suppress the catalytic function of kinase monomers and their dimerization with uninhibited partners are therefore a potentially useful therapeutic modality. 46 Certain pseudokinases that lack intrinsic enzyme function also exploit dimerization to regulate signaling pathways and may be amenable to pharmacological intervention through nucleotide-binding-site ligands that prevent dimerization. 47 The most advanced compound we studied showed nanomolar potency for biochemical inhibition of the kinase and RNase and, importantly, was highly selective for IRE1α over other kinases.…”

Synthesis and Functionalization of Imidazo[1,2‐b]Pyridazine by Means of Metal‐Catalyzed Cross‐Coupling Reactions

“…Another series of imidazo[1,2-b]pyridazin-8-amine kinase inhibitors were discovered by Collins et al. [100] The selective displacement of the 8-bromo substituent of imidazo[1,2-b] pyridazine 50 by (1-methylpiperidin-4-yl)methanamine gave the intermediate 51. Then, the subsequent Suzuki-Miyaura reaction with heteroaryl boronate gave the expected product 52 in 13 % yield (over two steps) (Scheme 26).…”