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Description

A cell-permeable imidazopyrazinyl-naphthalenyl-phenylurea compound that acts as an IRE1&,amp,amp,amp,amp,amp,alpha,-selective type II kinase inhibitor (IC50 = 0.6 &,amp,amp,amp,amp,amp,micro,M, IC50 &,amp,amp,amp,amp,amp,gt,10 &,amp,amp,amp,amp,amp,micro,M against Erk2, JNK2, JNK3, Pak4, Pim1, PKA) by targeting ATP-binding site in its inactive conformation. Stabilizing IRE1&,amp,amp,amp,amp,amp,alpha, kinase domain in an inactive conformation by KIRA6 prevents IRE1&,amp,amp,amp,amp,amp,alpha, oligomerization and subsequent RNase domain activity induction, resulting in effective inhibition against stress-induced cellular IRE1&,amp,amp,amp,amp,amp,alpha, oligomerization (5 mM DTT for 6 h +/1 &,amp,amp,amp,amp,amp,micro,M KIRA6) &,amp,amp,amp,amp,amp, phosphorylation (1 h 10 &,amp,amp,amp,amp,amp,micro,M, KIRA6 pretretament prior to 1 &,amp,amp,amp,amp,amp,micro,M Tg/586005 &,amp,amp,amp,amp,amp, 586006 for 2 h), XBP1 mRNA splicing (IC50 = 2 &,amp,amp,amp,amp,amp,micro,M, 1 h KIRA6 pretreatment prior to 0.5 &,amp,amp,amp,amp,amp,micro,g/mL Tm/654380 &,amp,amp,amp,amp,amp, 504570 for 8 h), Ins1 mRNA degradation (IC50 = 0.5 &,amp,amp,amp,amp,amp,micro,M, 1 hKIRA6 pretretament prior to 0.5 &,amp,amp,amp,amp,amp,micro,g/mL Tm for 12 h), and apoptosis (% annexin V + cells = 22% vs. 60% post 72 h 0.25 &,amp,amp,amp,amp,amp,micro,g/mL BFA/203729 &,amp,amp,amp,amp,amp, 500583 treatment with or without 0.5 &,amp,amp,amp,amp,amp,micro,M KIRA6, No BFA control = 16%) in rat insulinoma INS-1 cultures without significant cytotoxicity (up to 10 &,amp,amp,amp,amp,amp,micro,M for 72 h). Blockage of stress-induced apoptosis is similarly observed in primary human &,amp,amp,amp,amp,amp, murine islets cultures (0.5 &,amp,amp,amp,amp,amp,micro,g/mL Tm for 16 h +/ 0.5 &,amp,amp,amp,amp,amp,micro,M KIRA6) with a concomitant recovery of glucose-stimulated insulin secretion. KIRA6 is bioavailable via intraperitoneal injection in mice (Plasma Cmax/t1/2/AUC0-24 h = 3.3 &,amp,amp,amp,amp,amp,micro,M/3.90 h/14.3 &,amp,amp,amp,amp,amp,micro,M·h, 10 mg/kg BALB/c i.p.) in vivo with no apparent animal toxicity and is efficacious (5 or 10 mg/kg/12 h for 33 to 37 days) in reducing high blood glucose level due to chronic ER stress-induced &,beta, cell loss among Ins2+/Akita mice expressing proinsulin C96Y mutant with oxidative folding defect. Likewise, KIRA6 co-administration is shown to significantly reduce Rhodopsin mRNA degradation 96 h post Tm intraveal injection (2 &,amp,amp,amp,amp,amp,micro,L per eye, final vitreal [Tm] &,amp,amp,amp,amp,amp, [KIRA6] = 20 &,amp,amp,amp,amp,amp,micro,g/&,amp,amp,amp,amp,amp,micro,L &,amp,amp,amp,amp,amp, 10 &,amp,amp,amp,amp,amp,micro,M, respectively) in a rat model of acute photoreceptor loss in vivo, despite a rapid vitreal clearance (t1/2412510) that covalently modifies IRE1 RNase domain Lys907 in Tm-treated INS-1 cultures., A cell-permeable, bioavailable, non-toxic, imidazopyrazinyl-naphthalenyl-phenylurea based compound that acts as a potent, ATP-competitive, reversible, and selective inhibitor of IRE1&,alpha, kinase (IC50 = 600 nM). Exhibits good selectivity over ERK2, JNK2, JNK3, PIM1, PAK4, and PKA (IC50 &,gt,10 &,micro,M). Stabilizes the kinase domain of IRE1&,alpha, in an inactive conformation and blocks its oligomerization and thereby reduces RNase domain activity. Shown to block brefeldin A-(Cat. Nos. 203729 &, 500583) induced ER stress and apoptosis in INS-1 cells and tunicamycin (Cat. Nos. 654380 &, 504570)-induced apoptosis in &beta,-cells derived from C57BL/6 mice. Affords significant cytoprotection in combination with STF-083010 (Cat. No. 412510, 1 microM) and KIRA6 (50 nM). Systemic administration of KIRA6 in the Akita diabetic mice is shown to reduce their blood glucose levels, improve glucose tolerance, and conserve their &beta,-cell function. Preserves photoreceptor function in a transgenic rat model (P23H) of chronic ER stress-induced retinal degeneration, when administered intravitreally. Displays desirable pharmacokinetic properties with t1/2 = 3.9 h and moderate clearance rate of 22.4 ml/min/kg in BABL/c mice (10 mg/kg, i.p.).Please note that the molecular weight for this compound is batch-specific due to variable water content.