AZD5582 is a divalent AVPI motif-based Smac (DIABLO) mimetic (SMC) that acts a potent apoptosis protein repeat (BIR) domain-targeting antagonist against inhibitor of apoptosis proteins (IAPs) cIAP1/2 (BIR3 IC50 = 15/21 nM against 2.5 nM AbuRPFK-5FAM) and XIAP (BIR2/3 IC50 = 21/15 nM). AZD5582 abolishes cellular XIAP-caspase-9 interaction (1 μM, 4 hrs), induces cIAP1/2 degradation (EC50 = 0.1 nM, 1 hr) and apoptosis (GI50 <60 pM, 48 hrs) in MDA-MB-231 breast cancer cultures. AZD5582 causes substantial tumor regression by inducing cIAP1 degradation and apoptosis in tumor cells in MDA-MB-231 xenograft-bearing mice in vivo (3.0 mg/kg/wk i.v.).
Divalent Smac mimetic compound (SMC) as a potent BIR domain-targeting antagonist against inhibitor of apoptosis proteins (IAPs) cIAP1/2 & XIAP in vitro and in vivo.
Journal of medicinal chemistry, 56(24), 9897-9919 (2013-12-11)
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