Bivalent Smac Mimetics with a Diazabicyclic Core as Highly Potent Antagonists of XIAP and cIAP1/2 and Novel Anticancer Agents

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• 作者：Yuefeng Peng ; Haiying Sun ; Jianfeng Lu ; Liu Liu ; Qian Cai ; Rong Shen ; Chao-Yie Yang ; Han Yi ; Shaomeng Wang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：January 12, 2012
• 年：2012
• 卷：55
• 期：1
• 页码：106-114
• 全文大小：527K
• 年卷期：v.55,no.1(January 12, 2012)
• ISSN：1520-4804

文摘

Nonpeptidic, bivalent Smac mimetics designed based upon monovalent Smac mimetics with a diazabicyclic core structure bind to XIAP, cIAP1, and cIAP2 with low to subnanomolar affinities and are highly effective in antagonizing XIAP in cell-free functional assays. They efficiently induce the degradation of cIAP1 and cIAP2 in cancer cells at concentrations as low as 1 nM, activate caspase-3 and -8, and cleave PARP at 3鈥?0 nM. The most potent compounds in the series have IC₅₀ of 3鈥? nM in inhibition of cell growth in both MDA-MB-231and SK-OV-3 cell lines and are promising lead compounds for the development of a new class of cancer therapy.