SM-164: a novel, bivalent Smac mimetic that induces apoptosis and tumor regression by concurrent removal of the blockade of cIAP-1/2 and XIAP.
SM-164: a novel, bivalent Smac mimetic that induces apoptosis and tumor regression by concurrent removal of the blockade of cIAP-1/2 and XIAP.
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SM-164：一种新颖的二价SMAC模拟物，通过同时消除CIAP-1/2和XIAP的封锁来诱导凋亡和肿瘤消退。
DOI：
10.1158/0008-5472.can-08-2655
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发表时间：
2008-11-15
期刊：
影响因子：
11.2
通讯作者：
Wang S
中科院分区：
文献类型：
--
作者：
Lu J;Bai L;Sun H;Nikolovska-Coleska Z;McEachern D;Qiu S;Miller RS;Yi H;Shangary S;Sun Y;Meagher JL;Stuckey JA;Wang S
小分子Smac模拟物作为一类新型抗癌药物正在开发中。最近的研究表明，Smac模拟物靶向细胞凋亡抑制蛋白（cIAP）-1/2降解，并诱导肿瘤坏死因子-α（TNFα）依赖的肿瘤细胞凋亡。在这项研究中，我们研究了两种不同类型的新型Smac模拟物，单价SM-122和二价SM-164的作用机制和治疗潜力。我们的数据表明，通过Smac模拟物或小干扰RNA去除cIAP-1/2不足以产生强的TNFα依赖性凋亡诱导，X连锁凋亡抑制蛋白（XIAP）在抑制凋亡诱导中起关键作用。尽管SM-164在诱导cIAP-1/2降解方面比SM-122稍微更有效，但SM-164作为肿瘤细胞凋亡诱导剂的效力是SM-122的1，000倍，这归因于其在结合和拮抗XIAP方面的效力高得多。SM-164在MDA-MB-231异种移植肿瘤组织中诱导cIAP-1快速降解和强烈凋亡，并实现肿瘤消退，但在正常小鼠组织中无毒性。我们的研究为Smac模拟物的作用机制和凋亡抑制蛋白对凋亡的调节提供了进一步的见解。此外，我们的数据提供了证据，表明SM-164是一种有前途的新抗癌药物，可供进一步评估和开发。
Small-molecule Smac mimetics are being developed as a novel class of anticancer drugs. Recent studies have shown that Smac mimetics target cellular inhibitor of apoptosis protein (cIAP)-1/2for degradation and induce tumor necrosis factor-α (TNFα)–dependent apoptosis in tumor cells. In this study, we have investigated the mechanism of action and therapeutic potential of two different types of novel Smac mimetics, monovalent SM-122 and bivalent SM-164. Our data showed that removal of cIAP-1/2 by Smac mimetics or small interfering RNA is not sufficient for robust TNFα-dependent apoptosis induction, and X-linked inhibitor of apoptosis protein (XIAP) plays a critical role in inhibiting apoptosis induction. Although SM-164 is modestly more effective than SM-122 in induction of cIAP-1/2 degradation, SM-164 is 1,000 times more potent than SM-122 as an inducer of apoptosis in tumor cells, which is attributed to its much higher potency in binding to and antagonizing XIAP. SM-164 induces rapid cIAP-1 degradation and strong apoptosis in the MDA-MB-231 xenograft tumor tissues and achieves tumor regression, but has no toxicity in normal mouse tissues. Our study provides further insights into the mechanism of action for Smac mimetics and regulation of apoptosis by inhibitor of apoptosis proteins. Furthermore, our data provide evidence that SM-164 is a promising new anticancer drug for further evaluation and development.