Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany. German Cancer Consortium (DKTK), Heidelberg, Germany. German Cancer Research Center (DKFZ), Heidelberg, Germany.
Clin Cancer Res. 2015 Nov 15;21(22):5030-6. doi: 10.1158/1078-0432.CCR-15-0365.
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.
凋亡抑制蛋白（IAP）能够阻止细胞程序性死亡，在多种人类癌症中高表达，因此成为癌症药物开发的有吸引力的靶点。第二线粒体衍生的半胱氨酸天冬氨酸蛋白酶激活剂（Smac）模拟物是小分子抑制剂，可模拟 Smac，即 IAP 蛋白的内源性拮抗剂。临床前研究表明，Smac 模拟物可直接引发癌细胞死亡，或者更重要的是，增强肿瘤细胞对各种细胞毒性疗法的敏感性，包括常规化疗、放疗或新型药物。目前，几种 Smac 模拟物正在早期临床试验中作为单药或联合用药（即 GDC-0917/CUDC-427、LCL161、AT-406/ Debio1143、HGS1029 和 TL32711/ birinapant）进行评估。本文讨论了将 Smac 模拟物作为癌症治疗剂的开发在转化层面上的前景和一些挑战。
