SM-164 is a nonpeptide and ultrapotent antagonist of XIAP with IC50 value of 1.39 nM, over >7000 fold to the natural Smac AVPI peptide, for binding to BIR domains of XIAP. SM-164 induced apoptosis of HL-60 leukemia cell line at concentrations as low as 1 nM[1]. Treatment with SM-164 for 48h dose-dependently induced apoptosis in the MDA-MB-231 cancer cell line in a caspase-3– and caspase-8–dependent manner at concentration of 1, 10 and 100nM. SM-164 induced TNFα-dependent apoptosis post 48-hour treatment at concentration ranging in 1-100nM in HCT116 cells and induced cIAP-1 degradation post 1-hour treatment at concentration of 10nM and 100nM in MDA-MB-231 cells, which did not require degradation of XIAP. However, overexpression of XIAP could effectively attenuate the apoptosis induced by SM-164 in combination with TNFα. Administration of SM-164, i.v., daily, 5 days per week for 2 weeks, could achieve tumor regression of SCID mice bearing established MDA-MB-231 xenograft tumors at dose of both 1mg/kg and 5mg/kg, with rapid cIAP-1 degradation and robust apoptosis in tumor tissues observed. A minimal toxicity to mouse tissues post SM-164 treatment could also be observed[2].
作用机制
SM-164 can mimics Smac protein for targeting XIAP and competitively bind to XIAP containing both BIR2 and BIR3 domains.[1][2]
搜索
