Bai Longchuan, Smith David C, Wang Shaomeng
Comprehensive Cancer Center, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA; Department of Pharmacology, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA; Department of Medicinal Chemistry, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA.
Comprehensive Cancer Center, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA; Department of Pharmacology, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA; Department of Medicinal Chemistry, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA.
Pharmacol Ther. 2014 Oct;144(1):82-95. doi: 10.1016/j.pharmthera.2014.05.007. Epub 2014 May 16.
Apoptosis is a tightly regulated cellular process and faulty regulation of apoptosis is a hallmark of human cancers. Targeting key apoptosis regulators with the goal to restore apoptosis in tumor cells has been pursued as a new cancer therapeutic strategy. XIAP, cIAP1, and cIAP2, members of inhibitor of apoptosis (IAP) proteins, are critical regulators of cell death and survival and are attractive targets for new cancer therapy. The SMAC/DIABLO protein is an endogenous antagonist of XIAP, cIAP1, and cIAP2. In the last decade, intense research efforts have resulted in the design and development of several small-molecule SMAC mimetics now in clinical trials for cancer treatment. In this review, we will discuss the roles of XIAP, cIAP1, and cIAP2 in regulation of cell death and survival, and the design and development of small-molecule SMAC mimetics as novel cancer treatments.
细胞凋亡是一个受到严格调控的细胞过程,而细胞凋亡的调控异常是人类癌症的一个标志。以恢复肿瘤细胞中的细胞凋亡为目标,靶向关键的细胞凋亡调节因子已成为一种新的癌症治疗策略。凋亡抑制蛋白(IAP)家族成员XIAP、cIAP1和cIAP2是细胞死亡和存活的关键调节因子,也是新型癌症治疗的有吸引力的靶点。SMAC/DIABLO蛋白是XIAP、cIAP1和cIAP2的内源性拮抗剂。在过去十年中,大量的研究工作导致了几种小分子SMAC模拟物的设计和开发,目前这些模拟物正在进行癌症治疗的临床试验。在这篇综述中,我们将讨论XIAP、cIAP1和cIAP2在细胞死亡和存活调控中的作用,以及小分子SMAC模拟物作为新型癌症治疗方法的设计和开发。