Promises and Challenges of Smac Mimetics as Cancer Therapeutics
Promises and Challenges of Smac Mimetics as Cancer Therapeutics
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DOI：
10.1158/1078-0432.ccr-15-0365
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发表时间：
2015-11-15
影响因子：
11.5
通讯作者：
Fulda, Simone
中科院分区：
文献类型：
--
作者：
Fulda, Simone
细胞凋亡抑制剂（IAP）蛋白阻断程序性细胞死亡，并在各种人类癌症中高水平表达，因此使其成为癌症药物开发的有吸引力的靶点。半胱天冬酶的第二线粒体激活剂（Smac）模拟物是模拟IAP蛋白的内源性拮抗剂Smac的小分子抑制剂。临床前研究表明，Smac模拟物可以直接触发癌细胞死亡，或者更重要的是，使肿瘤细胞对各种细胞毒性疗法敏感，包括常规化疗，放疗或新型药物。目前，几种Smac模拟物在早期临床试验中作为单一疗法或合理组合（即，GDC-0917/CUDC-427、LCL161、AT-406/Debio1143、HGS 1029和TL32711/birinapant）。本文综述了利用Smac模拟物作为癌症治疗药物的前景以及在翻译界面上的一些挑战。(C)2015年AACR。
Inhibitor of Apoptosis (IAP) proteins block programmed cell death and are expressed at high levels in various human cancers, thus making them attractive targets for cancer drug development. Second mitochondrial activator of caspases (Smac) mimetics are small-molecule inhibitors that mimic Smac, an endogenous antagonist of IAP proteins. Preclinical studies have shown that Smac mimetics can directly trigger cancer cell death or, even more importantly, sensitize tumor cells for various cytotoxic therapies, including conventional chemotherapy, radiotherapy, or novel agents. Currently, several Smac mimetics are under evaluation in early clinical trials as monotherapy or in rational combinations (i.e., GDC-0917/CUDC-427, LCL161, AT-406/Debio1143, HGS1029, and TL32711/birinapant). This review discusses the promise as well as some challenges at the translational interface of exploiting Smac mimetics as cancer therapeutics. (C) 2015 AACR.