Laboratory of Cell Death and Cancer Research, Biology& Human Biology Departments, Faculty of Natural Sciences, University of Haifa, Haifa 3498838, Israel.
Cells. 2020 Mar 9;9(3):663. doi: 10.3390/cells9030663.
Inhibitors of apoptosis (IAPs) are a family of proteins that regulate cell death and inflammation. XIAP (X-linked IAP) is the only family member that suppresses apoptosis by directly binding to and inhibiting caspases. On the other hand, cIAPs suppress the activation of the extrinsic apoptotic pathway by preventing the formation of pro-apoptotic signaling complexes. IAPs are negatively regulated by IAP-antagonist proteins such as Smac/Diablo and ARTS. ARTS can promote apoptosis by binding and degrading XIAP via the ubiquitin proteasome-system (UPS). Smac can induce the degradation of cIAPs but not XIAP. Many types of cancer overexpress IAPs, thus enabling tumor cells to evade apoptosis. Therefore, IAPs, and in particular XIAP, have become attractive targets for cancer therapy. In this review, we describe the differences in the mechanisms of action between Smac and ARTS, and we summarize efforts to develop cancer therapies based on mimicking Smac and ARTS. Several Smac-mimetic small molecules are currently under evaluation in clinical trials. Initial efforts to develop ARTS-mimetics resulted in a novel class of compounds, which bind and degrade XIAP but not cIAPs. Smac-mimetics can target tumors with high levels of cIAPs, whereas ARTS-mimetics are expected to be effective for cancers with high levels of XIAP.
凋亡抑制蛋白（IAPs）是一组调节细胞死亡和炎症的蛋白质。XIAP（X 连锁 IAP）是唯一通过直接结合并抑制半胱天冬酶来抑制细胞凋亡的家族成员。另一方面，cIAPs 通过阻止促凋亡信号复合物的形成来抑制外在凋亡途径的激活。IAPs 被 IAP 拮抗剂蛋白（如 Smac/Diablo 和 ARTS）负调控。ARTS 通过结合并通过泛素蛋白酶体系统（UPS）降解 XIAP 来促进凋亡。Smac 可以诱导 cIAPs 降解，但不能诱导 XIAP 降解。许多类型的癌症过度表达 IAPs，从而使肿瘤细胞能够逃避凋亡。因此，IAPs，特别是 XIAP，已成为癌症治疗的有吸引力的靶点。在这篇综述中，我们描述了 Smac 和 ARTS 之间作用机制的差异，并总结了基于模拟 Smac 和 ARTS 开发癌症治疗方法的努力。几种 Smac 模拟小分子目前正在临床试验中进行评估。最初开发 ARTS 模拟物的努力产生了一类新型化合物，它们结合并降解 XIAP 但不降解 cIAPs。Smac 模拟物可以靶向具有高 cIAP 水平的肿瘤，而 ARTS 模拟物有望对 XIAP 水平高的癌症有效。
