SM-164 Anticancer agent

Description:

SM-164 is a bivalent mimetic of Smac with Ki values of 0.31 nM, 1.1 nM and 0.56 nM for cIAP-1, cIAP-2 and XIAP, respectively 1.SM-164 is developed as an anticancer agent.

Background:

SM-164 is a bivalent mimetic of Smac with Ki values of 0.31 nM, 1.1 nM and 0.56 nM for cIAP-1, cIAP-2 and XIAP, respectively.

SM-164 is developed as an anticancer agent. It plays its antitumor roles through inducing degradation of cellular inhibitor of apoptosis protein (cIAP)-1/2, antagonizing X-linked inhibitor of apoptosis protein (XIAP) and inducing TNFα-dependent apoptosis in tumor cells. SM-164 is a bivalent mimetic containing two SM-122 analogues. It binds to cIAP-1 protein containing bothBIR2 and BIR3 domains, cIAP-2 BIR3 protein and XIAP protein containing both BIR2 and BIR3 domains with Ki values of 0.31 nM, 1.1 nM and 0.56 nM, respectively. In tumor cells, treatment of SM-164 significantly reduced cIAP-1 level to undetectable levels (1 nM, 60 min), effectively antagonized cellular XIAP and enhanced TNFα secretion. In the MDA-MB-231 xenograft model, administration of SM-164 at dose of 5 mg/kg markedly decreased cIAP-1 level within 1 hour and activated caspase-8, caspase-9 and caspase-3 at 3 hour.

Animal models:

MDA-MB-231 xenograft tumor mice model

Applications:

12 h 1 nmol/L SM-164 treatment induces 32%, 33%, and 37% of the MDA-MB-231, SK-OV-3 and MALME-3M cells to undergo apoptosis. SM-164 also leads to cIAP-1 degradation in resistant cancer cell line and effectively antagonizes cellular XIAP. Moreover, 3 to 10 nmol/L SM-164 induces cell death with or without TNFα in all these sensitive cancer cell lines.