Sun Haiying, Stuckey Jeanne A, Nikolovska-Coleska Zaneta, Qin Dongguang, Meagher Jennifer L, Qiu Su, Lu Jianfeng, Yang Chao-Yie, Saito Naoyuki G, Wang Shaomeng
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
J Med Chem. 2008 Nov 27;51(22):7169-80. doi: 10.1021/jm8006849.
Small molecules designed to mimic the binding of Smac protein to X-linked inhibitor of apoptosis protein (XIAP) are being pursued as a promising new class of anticancer drugs. Herein, we report the design, synthesis, and comprehensive structure-activity relationship studies of a series of conformationally constrained bicyclic Smac mimetics. Our studies led to the discovery of a number of highly potent and cell-permeable Smac mimetics and yielded important new insights into their structure-activity relationship for their binding to XIAP and for their activity in inhibition of cancer cell growth. Determination of the crystal structure of one potent Smac mimetic, compound 21, in complex with XIAP BIR3 provides the structural basis for its high-affinity binding to XIAP and for the design of highly potent Smac mimetics.
旨在模拟Smac蛋白与X连锁凋亡抑制蛋白（XIAP）结合的小分子，正作为一类有前途的新型抗癌药物而被研究。在此，我们报告了一系列构象受限的双环Smac模拟物的设计、合成及全面的构效关系研究。我们的研究发现了许多高效且具有细胞渗透性的Smac模拟物，并为它们与XIAP结合的构效关系以及抑制癌细胞生长的活性提供了重要的新见解。一种强效Smac模拟物化合物21与XIAP BIR3复合物的晶体结构测定，为其与XIAP的高亲和力结合以及高效Smac模拟物的设计提供了结构基础。
