生物活性

• 描述AZD5582 is an IAP inhibitor with IC50 values of 15nM, 21nM and 15nM for cIAP1, cIAP2 and XIAP (measured by fluoresence polarization assays), respectively. Treatment with AZD5582 caused cIAP1 degradation with IC50 of 0.1nM and cell growth inhibition with GI50<0.06nM in MDA-MB-231 cells. And induction of cell apoptosis could be observed by AZD5582 at subnanomolar concentration. A single intravenous dose of AZD5582 caused dose (0.05-3mg/kg)- and time (4, 6 and 18h)-degradation of cIAP1 and increased cleaved caspase3 in mice bearing MDA-MB-231 xenografts, suggesting the pharmacodynamics of this compound in vivo. Intravenous injection with AZD5582 at dose of 0.1, 0.5 and 3mg/kg, once a week for 2 weeks, dose-dependently inhibited growth inhibition in the MDA-MB-231 xenograft efficacy model^[1]. AZD5582 can target cIAP1 to induce TNF-α-induced apoptosis accompanied with a decrease of Mcl-1 protein, a member of the Bcl-2 family, but not that of Bcl-2 and Bcl-xL^[2].
• 作用机制AZD5582 can bind potently to the BIR3 domains of cIAP1, cIAP2 and XIAP and cause cIAP1 degradation.^[1]

• 动物研究
  剂量	Mice[1] (i.v.): min = 0.1 mg/kg, max = 3 mg/kg
  给药途径	i.v.
  动物药代数据	Animal Rats[1] Dose 0.5 mg/kg Administration i.v. T1/2 0.5 ± 0.1 h AUC 166 ± 3 ng·h/ml CL 50 ± 0.8 ml/min/kg Vss 0.8 ± 0.1 L/kg