Potent Bivalent Smac Mimetics: Effect of the Linker on Binding to Inhibitor of Apoptosis Proteins (IAPs) and Anticancer Activity

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• 作者：Haiying Sun ; Liu Liu ; Jianfeng Lu ; Longchuan Bai ; Xiaoqin Li ; Zaneta Nikolovska-Coleska ; Donna McEachern ; Chao-Yie Yang ; Su Qiu ; Han Yi ; Duxin Sun ; Shaomeng Wang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：May 12, 2011
• 年：2011
• 卷：54
• 期：9
• 页码：3306-3318
• 全文大小：1168K
• 年卷期：v.54,no.9(May 12, 2011)
• ISSN：1520-4804

文摘

We have synthesized and evaluated a series of nonpeptidic, bivalent Smac mimetics as antagonists of the inhibitor of apoptosis proteins and new anticancer agents. All these bivalent Smac mimetics bind to full-length XIAP with low nanomolar affinities and function as ultrapotent antagonists of XIAP. While these Smac mimetics bind to cIAP1/2 with similar low nanomolar affinities, their potencies to induce degradation of cIAP1/2 proteins in cells differ by more than 100-fold. The most potent bivalent Smac mimetics inhibit cell growth with IC₅₀ from 1 to 3 nM in the MDA-MB-231 breast cancer cell line and are 100 times more potent than the least potent compounds. Determination of intracellular concentrations for several representative compounds showed that the linkers in these bivalent Smac mimetics significantly affect their intracellular concentrations and hence the overall cellular activity. Compound 27 completely inhibits tumor growth in the MDA-MB-231 xenografts while causing no signs of toxicity in the animals.