A Potent and Orally Active Antagonist (SM-406/AT-406) of Multiple Inhibitor of Apoptosis Proteins (IAPs) in Clinical Development for Cancer Treatment

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• 作者：Qian Cai ; Haiying Sun ; Yuefeng Peng ; Jianfeng Lu ; Zaneta Nikolovska-Coleska ; Donna McEachern ; Liu Liu ; Su Qiu ; Chao-Yie Yang ; Rebecca Miller ; Han Yi ; Tao Zhang ; Duxin Sun ; Sanmao Kang ; Ming Guo ; Lance Leopold ; Dajun Yang ; Shaomeng Wang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：April 28, 2011
• 年：2011
• 卷：54
• 期：8
• 页码：2714-2726
• 全文大小：1250K
• 年卷期：v.54,no.8(April 28, 2011)
• ISSN：1520-4804

文摘

We report the discovery and characterization of SM-406 (compound 2), a potent and orally bioavailable Smac mimetic and an antagonist of the inhibitor of apoptosis proteins (IAPs). This compound binds to XIAP, cIAP1, and cIAP2 proteins with K_i of 66.4, 1.9, and 5.1 nM, respectively. Compound 2 effectively antagonizes XIAP BIR3 protein in a cell-free functional assay, induces rapid degradation of cellular cIAP1 protein, and inhibits cancer cell growth in various human cancer cell lines. It has good oral bioavailability in mice, rats, non-human primates, and dogs, is highly effective in induction of apoptosis in xenograft tumors, and is capable of complete inhibition of tumor growth. Compound 2 is currently in phase I clinical trials for the treatment of human cancer.