SM-164 is a cell-permeable bivalent mimetic of Smac and an inhibitor of X-linked inhibitor of apoptosis (XIAP).1 It binds to BIR2 and BIR3 domain-containing XIAP with an IC50 value of 1.39 nM and interacts with both domains. SM-164 inhibits growth (IC50 = 1 nM), as well as activates caspase-3 and caspase-9, and induces cleavage of the caspase-3 substrate poly(ADP-ribose)-polymerase (PARP), a marker of apoptosis, in HL-60 leukemia cells when used at a concentration of 10 nM. It also reduces tumor volume by 80% in a 2LMP breast cancer mouse xenograft model when administered at a dose of 5 mg/kg in combination with TNF-related apoptosis-inducing ligand (TRAIL).2
1.Sun, H., Nikolovska-Coleska, Z., Lu, J., et al.Design, synthesis, and characterization of a potent, non-peptide, cell-permeable, bivalent Smac mimetic that concurrently targets both the BIR2 and BIR3 domains in XIAPJ. Am. Chem. Soc.129(49)15279-15294(2007) 2.Lu, J., McEachern, D., Sun, H., et al.Therapeutic potential and molecular mechanism of a novel, potent, nonpeptide, Smac mimetic SM-164 in combination with TRAIL for cancer treatmentMol. Cancer Ther.10(5)902-914(2011)