SM-164

SM-164 binds to XIAP protein containing both the BIR2 and BIR3 domains (IC50: 1.39 nM) . It acts as an extremely potent antagonist of XIAP. SM-164 binds to XIAP being 300 and 7000-times more potent than its monovalent counterparts and the natural Smac AVPI peptide, respectively. The binding affinities of SM-164 to XIAP, cIAP-1, and cIAP-2 proteins are determined using fluorescence-polarization based assays. SM-164 concurrently interacts with both BIR domains in XIAP and functions as an ultra-potent antagonist of XIAP in both cell-free functional and cell-based assays. SM-164 targets cellular XIAP and effectively induces apoptosis at concentrations as low as 1 nM in leukemia cancer cells while having minimal toxicity to normal human primary cells at 10,000 nM. SM-164 has a Ki value of 0.56 nM to XIAP protein containing both BIR2 and BIR3 domains. SM-164 has a Ki value of 0.31 nM to a cIAP-1 protein containing both BIR2 and BIR3 domains. SM-164 binds to cIAP-2 BIR3 protein with Ki values of 1.1 nM.SM-164 is highly effective in the inhibition of tumor growth and capable of achieving tumor regression in the MDA-MB-231 xenograft model. SM-164 (1 mg/kg) treatment fully inhibits tumor growth during the treatment. SM-164 (5 mg/kg) treatment reduces the tumor volume from 147±54 mm3 at the beginning of the treatment (day 25) to 54±32 mm3 at the end of the treatment (day 36), a reduction of 65%. The strong antitumor activity by SM-164 is long-lasting and not transient. SM-164 (5 mg/kg) is statistically more effective than Taxotere at the end of the treatment (P<0.01) or when the tumor size in the control group reached 750 mm3 (P<0.02) .