Kira8 is a mono-selective IRE1α inhibitor that allosterically attenuates IRE1α's RNase[1].
Kira8 blocks IRE1α oligomerization, and potently inhibits IRE1α RNase activity against XBP1 and Ins2 RNAs. Kira8 more potently reduces IRE1α-driven apoptosis in INS-1 cells than KIRA6 and also reverses XBP1 splicing promoted by GNF-2[1].
Kira8 efficaciously reverses established diabetes in non-obese diabetic (NOD) mice by sparing β-cells and preserving their physiological function. Kira8 is first tested in 3-week-old male pre-diabetic Akita mice by i.p. daily dosing of 50 mg/kg, whereupon significant reduction of hyperglycemia becomes apparent over several weeks. Then Kira8 (50 mg/kg) is tested in the complex NOD. Showing target engagement, one week treatment of pre-diabetic NODs with Kira8 leads to significant reductions in islet XBP1 splicing and TXNIP mRNAs, and preserved Ins1/Ins2, BiP and MANF mRNAs[1].
[1]. Morita S, et al. Targeting ABL-IRE1α Signaling Spares ER-Stressed Pancreatic β Cells to Reverse Autoimmune Diabetes. Cell Metab. 2017 Apr 4;25(4):883-897.e8.