MKC3946 is a potent and soluble IRE1α inhibitor, used for cancer research. In Vitro: MKC–3946 blocks XBP1 mRNA splicing and exhibits cytotoxicity against AML cells. MKC–3946 inhibits XBP1S expression induced by tunicamycin (TM) in NB4 cells (B) and AML sample from patients. MKC–3946 prevents the splicing of the XBP1 mRNA in response to ER stress caused by mutant proinsulin production. MKC–3946 is an IRE1α endoribonuclease domain inhibitor that blocks XBP1 mRNA splicing and triggers modest growth inhibition in MM cells. MKC–3946 inhibits XBP1s expression induced by Tm in a dose–dependent manner, but does not affect phosphorylation of IRE1α. MKC–3946 blocks XBP1 splicing and enhances cytotoxicity induced by bortezomib or 17–AAG. MKC–3946 (10μM) enhances ER stress–mediated apoptosis induced by bortezomib or 17–AAG, and enhances cytotoxicity of ER stressors, even in the presence of BMSCs or exogenous IL–6. In Vivo: MKC–3946 (100 mg/kg, i.p.) inhibits XBP1 splicing in a model of ER stress in vivo, associated with significant growth inhibition of MM cells, alone or with bortezomib. MKC–3946 significantly reduces MM tumor growth in the treatment versus control group. Inhibition of XBP1 splicing by MKC–3946 is associated with decreased MM growth in vivo, alone or in combination with bortezomib.