IXA4

• CAT Number: I044433
• CAS Number: 1185329-96-7
• Molecular Formula: C24H28N4O4
• Molecular Weight: 436.50
• Purity: ≥95%
• Synonyms: N-[1-[2-[methyl-[2-(4-methylphenoxy)ethyl]amino]-2-oxoethyl]pyrazol-4-yl]-3-phenoxypropanamide
• InChI: InChI=1S/C24H28N4O4/c1-19-8-10-22(11-9-19)32-15-13-27(2)24(30)18-28-17-20(16-25-28)26-23(29)12-14-31-21-6-4-3-5-7-21/h3-11,16-17H,12-15,18H2,1-2H3,(H,26,29)
• InChIKey: ZVSKMVAWWBSNOY-UHFFFAOYSA-N
• SMILES: CC1=CC=C(C=C1)OCCN(C)C(=O)CN2C=C(C=N2)NC(=O)CCOC3=CC=CC=C3

IXA4 is a highly selective, non-toxic IRE1/XBP1s activator. IXA4 activates IRE1/XBP1s signaling without globally activating the unfolded protein response (UPR) or other stress-responsive signaling pathways (e.g., the heat shock response or oxidative stress response). IXA4 reduces secretion of APP through IRE1 activation[1].
IXA4 (10 μM; 4 hours) selectively upregulates XBP1s mRNA, relative to genes regulated by ATF6 (e.g., BiP) or PERK (e.g., CHOP), in other cell lines including Huh7 and SHSY5Y cells[1].
IXA4 (10μM; 18 hours) reduces Aβ levels 50% in conditioned media prepared on CHO7PA2 cells expressing the V717F APP (APPV717F) mutant[1].
IXA4 rescues mitochondrial defects in SH-SY5Y cells expressing disease-relevant APP mutants. IXA4 (10μM; 4 hours) promotes adaptive IRE1/XBP1s signaling, but not RIDD, following 4 hrs of treatment in HEK293T cells[1].
IXA4 also promotes selective transcriptional remodeling of ER proteostasis pathways, relative to cytosolic or mitochondrial pathways[1].

Reference

[1]. Grandjean JMD, et al. Pharmacologic IRE1/XBP1s activation confers targeted ER proteostasis reprogramming. Nat Chem Biol. 2020;16(10):1052-1061.
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