532281 IRE1 Inhibitor IV, KIRA6 - Calbiochem

532281
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      Overview

      Replacement Information

      Key Specifications Table

      Empirical Formula
      C₂₈H₂₅F₃N₆O

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      5.32281.0001
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          Glass bottle 10 mg
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          Description
          OverviewA cell-permeable, bioavailable, non-toxic, imidazopyrazinyl-naphthalenyl-phenylurea based compound that acts as a potent, ATP-competitive, reversible, and selective inhibitor of IRE1α kinase (IC50 = 600 nM). Exhibits good selectivity over ERK2, JNK2, JNK3, PIM1, PAK4, and PKA (IC50 > 10 µM). Stabilizes the kinase domain of IRE1α 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 β-cells derived from C57BL/6 mice. Affords significant cytoprotection in combination with STF-083010 (Cat. No. 412510, 1 µM) 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 β-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.
          Catalogue Number532281
          Brand Family Calbiochem®
          Synonyms1-(4-(8-Amino-3-tert-butylimidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-3-(3-(trifluoromethyl)phenyl)urea, Kinase-Inhibiting RNase Attenuator 6, IRE1α Kinase Inhibitor
          References
          ReferencesGhosh, R., et al. 2014. Cell. 158, 534.
          Product Information
          FormOff-white to brown powder
          Hill FormulaC₂₈H₂₅F₃N₆O
          Chemical formulaC₂₈H₂₅F₃N₆O
          ReversibleY
          Applications
          Biological Information
          Primary TargetIRE1α kinase
          Purity≥95% by HPLC
          Physicochemical Information
          Cell permeableY
          Dimensions
          Materials Information
          Toxicological Information
          Safety Information according to GHS
          Safety Information
          Product Usage Statements
          Storage and Shipping Information
          Ship Code Ambient Temperature Only
          Toxicity Standard Handling
          Storage +2°C to +8°C
          Protect from Light Protect from light
          Do not freeze Ok to freeze
          Special InstructionsFollowing reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.
          Packaging Information
          Packaged under inert gas Packaged under inert gas
          Transport Information
          Supplemental Information
          Specifications

          Documentation

          IRE1 Inhibitor IV, KIRA6 - Calbiochem SDS

          Title

          Safety Data Sheet (SDS) 

          References

          Reference overview
          Ghosh, R., et al. 2014. Cell. 158, 534.

          Brochure

          Title
          NPI Flyer- Epigenetics and Nuclear Function Feature (EMD)
          New Products - Antibodies, Small Molecule, Inhibitors

          Technical Info

          Title
          White Paper: Further considerations of antibody validation and usage. (EMD)
          Data Sheet

          Note that this data sheet is not lot-specific and is representative of the current specifications for this product. Please consult the vial label and the certificate of analysis for information on specific lots. Also note that shipping conditions may differ from storage conditions.

          Revision16-November-2016 JSW
          Synonyms1-(4-(8-Amino-3-tert-butylimidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-3-(3-(trifluoromethyl)phenyl)urea, Kinase-Inhibiting RNase Attenuator 6, IRE1α Kinase Inhibitor
          DescriptionA cell-permeable imidazopyrazinyl-naphthalenyl-phenylurea compound that acts as an IRE1α-selective type II kinase inhibitor (IC50 = 0.6 µM; IC50 >10 µM against Erk2, JNK2, JNK3, Pak4, Pim1, PKA) by targeting ATP-binding site in its inactive conformation. Stabilizing IRE1α kinase domain in an inactive conformation by KIRA6 prevents IRE1α oligomerization and subsequent RNase domain activity induction, resulting in effective inhibition against stress-induced cellular IRE1α oligomerization (5 mM DTT for 6 h +/1 µM KIRA6) & phosphorylation (1 h 10 µM; KIRA6 pretretament prior to 1 µM Tg/586005 & 586006 for 2 h), XBP1 mRNA splicing (IC50 = 2 µM; 1 h KIRA6 pretreatment prior to 0.5 µg/mL Tm/654380 & 504570 for 8 h), Ins1 mRNA degradation (IC50 = 0.5 µM; 1 hKIRA6 pretretament prior to 0.5 µg/mL Tm for 12 h), and apoptosis (% annexin V + cells = 22% vs. 60% post 72 h 0.25 µg/mL BFA/203729 & 500583 treatment with or without 0.5 µM KIRA6; No BFA control = 16%) in rat insulinoma INS-1 cultures without significant cytotoxicity (up to 10 µM for 72 h). Blockage of stress-induced apoptosis is similarly observed in primary human & murine islets cultures (0.5 µg/mL Tm for 16 h +/ 0.5 µM 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 µM/3.90 h/14.3 µM·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 β 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 µL per eye, final vitreal [Tm] & [KIRA6] = 20 µg/µL & 10 µM, respectively) in a rat model of acute photoreceptor loss in vivo, despite a rapid vitreal clearance (t1/2 <60 h). Synergistic cytoprotection is demonstrated when combined with STF-083010 (Cat. No. 412510) that covalently modifies IRE1 RNase domain Lys907 in Tm-treated INS-1 cultures.
          FormOff-white to brown powder
          Intert gas (Yes/No) Packaged under inert gas
          Chemical formulaC₂₈H₂₅F₃N₆O
          Purity≥95% by HPLC
          SolubilityDMSO (50 mg/ml). Use only fresh DMSO for reconstitution.
          Storage +2°C to +8°C
          Protect from light
          Do Not Freeze Ok to freeze
          Special InstructionsFollowing reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.
          Toxicity Standard Handling
          ReferencesGhosh, R., et al. 2014. Cell. 158, 534.