MKC-3946 is IRE1α endoribonuclease domain inhibitor. It inhibited basal XBP1 splicing in RPMI 8226 cells treated with tunicamycin dose-dependently at concentration<10μM post 3h, but did not affect phosphorylation of Ire1α. Consistent with downstream the inhibition of XBP1 splicing by MKC-3946, the expression of XBP1 target genes, SEC61A1, p58IPK, and ERdj4, were decreased. MKC-3946 triggered modest growth inhibition in MM cell lines and significantly enhanced cytotoxicity induced by bortezomib or 17-AAG, even in the presence of bone marrow stromal cells or exogenous IL-6. The ER stress induction by bortezomib and 17-AAG could be blocked by MKC-3946. Apoptosis induced by these agents was enhanced by MKC-3946, associated with increased CHOP. Administration of MKC-3946 at dose of 50mg/kg, i.p., inhibited XBP1 splicing in a model of ER stress induced by tunicamycin in vivo. Daily administration of MKC-3946 at dose of 100mg/kg, i.p., inhibited tumor growth in SCID mice xenograft RPMI 8226 cells and improved the survival level of the mice. Combination of MKC3946 with bortezomib could potentiated these efficiency[2].
搜索
