Uses
The IRE1 pathway is a component of the unfolded protein response that senses unfolded proteins via an ER luminal domain that becomes oligomerized during stress. It is associated with promoting cell survival through the activity of the IRE1α RNase, whose activity upregulates proteins that enhance ER protein folding and quality control. However, under high ER stress, the IRE1α RNase becomes hyperactive and is less discriminant in its substrate specificity, endonucleolytically cleaving many additional mRNAs that localize to the ER membrane, leading to cell proliferation blocks, inflammation, and apoptosis. KIRA6 is an ATP-competitive IRE1α kinase inhibiting RNase attenuator (KIRA) that allosterically inhibits IRE1α RNase kinase activity (IC50 = 0.6 μM) and prevents oligomerization. It has been shown to inhibit IRE1α in vivo and to promote cell survival under ER stress. At 20 μg/ml, KIRA6 is reported to preserve photoreceptor functional viability in rat models of ER stress-induced retinal degeneration. At 5 mg/kg, it has also been shown to preserve pancreatic β cells, increase insulin, and reduce hyperglycemia in Akita diabetic mice.[Cayman Chemical]
Biological Activity
KIRA6 can inhibited KIT at a similar concentration range. Direct binding measurements revealed that GSK414 associated more tightly than KIRA6 to the KIT cytoplasmic domain. On the other hand, it probably through competitive binding protected KIT from GSK414-mediated degradation.
in vitro
In INS-1 cells, KIRA6 inhibits IRE1α auto-phosphorylation by Tg and XBP1 mRNA splicing by Tm in a dose-dependent manner.
in vivo
Intravitreally, KIRA6 preserves photoreceptor functional viability in rat models of ER stress-induced retinal degeneration. Systemically, KIRA6 preserves pancreatic β-cells, increases insulin, and reduces hyperglycemia in Akita diabetic mice. It inhibits IRE1α in vivo to preserve cell viability and function in diverse cells and rodent tissues experiencing ER stress. The pharmacokinetic profile of KIRA6 in BALB/c mice intraperitoneally (i.p.) dosed at 10 mg/kg shows good drug plasma AUC levels (AUC 0-24h = 14.3 μM*h) with moderate clearance (22.4 mL/min/kg). Drug half-life is 3.90 hours, Cmax is 3.3 μM, and plasma levels at 4 and 8hr are 1.2 μM and 0.33 μM, respectively.
