412512
IRE1 Inhibitor III, 4μ8C
IRE1 Inhibitor III, CAS 14003-96-4, is a cell-permeable. Covalent inhibitor of IRE1 RNase activity (IC₅₀ = 550 and 45 nM, respectively, with 0 & 16 min preincubation in RNA cleavage assays).
Synonym(s):
IRE1 Inhibitor III, 4μ8C, 8-Formyl-7-hydroxy-4-methylcoumarin, 7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde, ER-to-Nucleus Signaling 1 Inhibitor III, Inositol-Reguiring Protein 1 Inhibitor III
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All Photos(2)
About This Item
Empirical Formula (Hill Notation):
C11H8O4
CAS Number:
Molecular Weight:
204.18
MDL number:
UNSPSC Code:
12352200
NACRES:
NA.28
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Quality Level
assay
≥95% (HPLC)
form
powder
manufacturer/tradename
Calbiochem®
storage condition
OK to freeze
protect from light
color
yellow
solubility
DMSO: 25 mg/mL
shipped in
ambient
storage temp.
2-8°C
SMILES string
O=C(C=C1C)OC2=C1C=CC(O)=C2C=O
InChI
1S/C11H8O4/c1-6-4-10(14)15-11-7(6)2-3-9(13)8(11)5-12/h2-5,13H,1H3
InChI key
RTHHSXOVIJWFQP-UHFFFAOYSA-N
General description
A cell-permeable coumarin o-hydroxyaldehyde compound that inhibits IRE1 RNase activity in a time- and dose-dependent manner (IC50 = 550, 230, 180, 100, and 45 nM, respectively, with 0, 2, 4, 8, 16, min drug preincubation in FRET-based RNA cleavage assays) by covalently targeting IRE1 Lys907 via Schiff base formation, effectively preventing ER stress-induced site-specific mRNA splicing as well as RIDD (Regulated IRE1-Dependent Degradation) mRNA degradation (IC50 = 6.9 and 4.1 µM, respectively, against Xbp1 splicing and Scara3 degradation) in MEF cultures following Tunicamycin (Cat. No. 654380) treatment. Also demonstrated to inhibit ER capacity expansion (Effective conc. 32 µM) and amylase secretion (IC50<2 µM) upon stress induction by Dexamethasone (Cat. No. 265005) treatment in rat AR42J tumoral acinar pancreatic cells. Structural analysis reveals that the reduced water accessibility to Lys907 in IRE1 native conformation accounts for the unusual stability of Lys907 Schiff base formation and forms the basis of selective IRE1 RNase inhibition by 4μ8C and STF083010 (Cat. No. 412510). Although 4μ8C, but not STF083010, is also shown to inhibit IRE1 autophosphorylation by Schiff base formation with IRE1 Lys599 in the absence of ADP, cellular nucleotide prevents 4μ8C from targeting IRE1 Lys599 and inhibiting IRE1 kinase activity intracellularly.
A cell-permeable coumarin o-hydroxyaldehyde that inhibits IRE1 RNase activity in a time- and dose-dependent manner (IC50 = 550 and 45 nM, respectively, with 0 and 16 min drug preincubation in RNA cleavage assays) by covalently targeting IRE1 Lys907 via Schiff base formation, effectively preventing ER stress-induced site-specific mRNA splicing as well as RIDD (Regulated IRE1-Dependent Degradation) mRNA degradation (IC50 = 6.9 and 4.1 µM, respectively, against Xbp1 splicing and Scara3 degradation) in MEF cultures following Tunicamycin (Cat. No. 654380) treatment. Comparing to STF083010 (Cat. No. 412510), 4μ8C is also shown to inhibit IRE1 autophosphorylation in cell-free assays via Schiff base formation with IRE1 Lys599 in the absence of ADP, however cellular nucleotide prevents 4μ8C from targeting IRE1 Lys599 intracellularly.
Biochem/physiol Actions
Cell permeable: yes
Primary Target
IRE1
IRE1
Reversible: yes
Packaging
Packaged under inert gas
Warning
Toxicity: Standard Handling (A)
Reconstitution
Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months.
Other Notes
Cross, B.C.S., et al. 2012. Proc. Natl. acad. Sci. USA109, E869.
Legal Information
CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany
wgk_germany
WGK 3
flash_point_f
Not applicable
flash_point_c
Not applicable
Certificates of Analysis (COA)
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