KIRA6 allosterically inhibits IRE1α RNase kinase activity with an IC50 of 0.6 uM.
KIRA6 dose-dependently inhibits IRE1α (WT) kinase activity, XBP1 RNA cleavage, Ins2 RNA cleavage and oligomerization. KIRA6 strongly inhibits JNK phosphorylation from IRE1α hyperactivation or ER stress. Also, KIRA6 dose-dependently inhibits Ins1 mRNA decay, proinsulin depletion, and apoptosis from IRE1α hyperactivation. In INS-1 cells, KIRA6 inhibits IRE1α auto-phosphorylation by Tg and XBP1 mRNA splicing by Tm in a dose-dependent manner. KIRA6 reduces ER stress-induced death of cultured cells and in pancreatic islet explants[1].
KIRA6 has negligible toxicity up to 10 uM, providing a favorable therapeutic index to test cytoprotection. KIRA6 in BALB/c mice intraperitoneally (i.p.) dosed at 10 mg/kg shows good drug plasma AUC levels with moderate clearance (22.4 mL/min/kg). Drug half-life is 3.90 hours, Cmax is 3.3 uM, and plasma levels at 4 and 8hr are 1.2 uM and 0.33 uM, respectively. Intravitreal co-injection of KIRA6 with Tm significantly reduces XBP1 splicing, TXNIP induction, and decay of the ER-localized photoreceptor-specific Rhodopsin mRNA. KIRA6 dose-dependently inhibits Rhodopsin RNA cleavage by IRE1α. Concomitant with blockage of Terminal UPR outputs, co-injection of KIRA6 in the Tm model reduces photoreceptor loss by Optical Coherence Tomography (OCT) and histology. KIRA6 substantially protects against loss of ERG responsiveness, significantly preserving both a- and b-wave amplitudes[1].
References:
[1]. Ghosh R, et al. Allosteric inhibition of the IRE1α RNase preserves cell viability and function during endoplasmic reticulum stress. Cell. 2014 Jul 31;158(3):534-48.