IXA4

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].

Signaling Pathways >> Cell Cycle/DNA Damage >> IRE1

Research Areas >> Neurological Disease

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].

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