ATP-competitive, potent and selective IRE1α kinase inhibitor that attenuates IRE1α endonuclease activity in vitro and in vivo.
KIRA8 is an ATP-competitive, potent and selective IRE1α kinase inhibitor (IRE1α/β Ki = 2/120 nM) that attenuates IRE1α endonuclease activity (IRE1α/β IC50 = 5/55 nM) with good kinome selectivity. KIRA8 inhibits thapsigargin-induced UPR (IC50 = 99 nM; HT1080 XBP1-Luc cells) and shows therapeutic efficacy in murine models of type 1 diabetes (T1D), pulmonary fibrosis, multiple myeloma (MM), and pancreatic neuroendocrine tumors (PanNET) in vivo (30-50 mg/kg/day i.p.).
In cells experiencing unrelieved endoplasmic reticulum (ER) stress, the ER transmembrane kinase/endoribonuclease (RNase)-IRE1α-endonucleolytically degrades ER-localized mRNAs to promote apoptosis. Here we find that the ABL family of tyrosine kinases rheostatically enhances IRE1α's enzymatic activities, thereby potentiating ER stress-induced apoptosis. During
ACS chemical biology, 14(12), 2595-2605 (2019-10-15)
The dual kinase endoribonuclease IRE1 is a master regulator of cell fate decisions in cells experiencing endoplasmic reticulum (ER) stress. In mammalian cells, there are two paralogs of IRE1: IRE1α and IRE1β. While IRE1α has been extensively studied, much less
Endoplasmic reticulum stress (ER stress) has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a disease of progressive fibrosis and respiratory failure. ER stress activates a signaling pathway called the unfolded protein response (UPR) that either restores homeostasis
Proceedings of the National Academy of Sciences of the United States of America, 116(33), 16420-16429 (2019-08-03)
Multiple myeloma (MM) arises from malignant immunoglobulin (Ig)-secreting plasma cells and remains an incurable, often lethal disease despite therapeutic advances. The unfolded-protein response sensor IRE1α supports protein secretion by deploying a kinase-endoribonuclease module to activate the transcription factor XBP1s. MM
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