KIRA8

**KIRA8** is a potent, monoselective small molecule inhibitor of IRE1α (also known as ERN1), a key endoplasmic reticulum (ER) stress sensor protein. It allosterically attenuates IRE1α's RNase activity with an IC50 of 5.9 nM, blocking IRE1α oligomerization and inhibiting RNase-mediated decay (RIDD) of mRNAs such as XBP1 and Ins2, while more effectively inducing IRE1α-driven apoptosis compared to related compounds like KIRA6. Preclinical studies demonstrate efficacy in reversing established fibrosis, protecting β-cells in diabetes models (e.g., reducing hyperglycemia in Akita and NOD mice via intraperitoneal dosing at 50 mg/kg), inhibiting cell growth and promoting apoptosis in pituitary neuroendocrine tumors and pancreatic ductal adenocarcinoma cells, and reducing transitional alveolar type 2 cell states in lung fibrosis models. Originally developed through academic research, it is available as a research tool from suppliers like TargetMol and MedKoo, with potential applications in ER stress-related diseases including diabetes, fibrosis, and cancers.