4µ8C | IRE1 ribonuclease inhibitor

4μ8C (14003-96-4) is a selective inhibitor of IRE1α ribonuclease (RNase) activity (IC₅₀ = 60 nM). Covalently binds to lysine 907 in the IRE1 endonuclease domain, blocking substrate access to the active site of IRE1α and inactivating both XBP1 splicing and IRE1α-mediated mRNA degradation but not IRE1 kinase activity.¹ Inhibits IRE1α in response to hypoxia or other ER stress-inducing agents but has no effect on proliferation or clonogenic survival of hypoxic cells.² Blocks production of IL-4, IL-5 and IL-13 production in T cells.³ 4μ8C prevents the splicing of the XBP1 mRNA in response to ER stress caused by mutant proinsulin production in pancreatic β-cells.⁴

References/Citations:

1) Cross et al. (2012), The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule; Proc. Natl. Acad. Sci. USA, 109 E869
2) Cojocari et al. (2013), New small molecule inhibitors of UPR activation demonstrate that PERK, but not IRE1α signaling is essential for promoting adaptation and survival to hypoxia;  Radiother. Oncol., 108 541
3) Kemp et al. (2013), The serine-threonine kinase inositol-requiring enzyme 1α (IRE1α) promotes IL-4 production in T helper cells; J. Biol. Chem., 288 33272
4) Zhang et al. (2014), IRE1 inhibition perturbs the unfolded protein response in a pancreatic β-cell line expressing mutant proinsulin, but does not sensitize the cells to apoptosis;  BMC Cell Biol., 15 29