Design of small-molecule Smac mimetics as IAP antagonists.
Design of small-molecule Smac mimetics as IAP antagonists.
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DOI：
10.1007/82_2010_111
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发表时间：
2010-12
影响因子：
--
通讯作者：
Shaomeng Wang
中科院分区：
文献类型：
--
作者：
Shaomeng Wang
Smac/DIABLO是在2000年发现的一种响应凋亡刺激而从线粒体释放到胞质溶胶中的蛋白，通过直接结合作为X连锁凋亡抑制蛋白（XIAP）和几种其他IAP蛋白的内源性拮抗剂发挥作用。Smac和IAP之间的相互作用涉及Smac的N-末端上的AVPI四肽结合基序和这些IAP蛋白表面上的明确的凹槽，为小分子Smac模拟物的设计提供了理想的位点。有效的和细胞可渗透的小分子Smac模拟物提供了强大的药理学工具的IAP蛋白的细胞凋亡的调节的研究，和几个这样的化合物，现在在早期的临床试验作为新的抗癌药物。
Smac/DIABLO, discovered in 2000 as a protein released from mitochondria into the cytosol in response to apoptotic stimuli, functions as an endogenous antagonist of X-linked inhibitor of apoptosis protein (XIAP) and several other IAP proteins through direct binding. The interaction between Smac and IAPs involves the AVPI tetrapeptide binding motif on the N-terminus of Smac and a well-defined groove on the surface of these IAP proteins, providing an ideal site for the design of small-molecule Smac mimetics. Potent and cell-permeable small-molecule Smac mimetics have provided powerful pharmacological tools for study of the regulation of apoptosis by IAP proteins, and several such compounds are now in early clinical trials as new anticancer agents.