Cho Young Sik
College of Pharmacy, Keimyung University, Dalseo-gu, Daegu 704-701, Republic of Korea.
Int J Mol Med. 2014 Jun;33(6):1401-6. doi: 10.3892/ijmm.2014.1716. Epub 2014 Mar 27.
In response to overwhelming external stimuli, cells are forced to die in different ways. By default, cells are prone to apoptosis, a programmed cell death through the activation of the caspase cascade. However, this process would be blocked if one of the proteins involved in executing apoptosis was genetically impaired or chemically inhibited, or if the apoptotic machinery was not properly operated under specific conditions, such as ischemia and microbial infection. To address these issues, the paradigm of programmed cell death needs to be revised; thus, an alternative form of cell death, programmed necrosis (termed necroptosis, through the caspase-independent pathway), which is distinct from apoptosis in many aspects, has recently been adopted. There is much interest in programmed necrosis as it is very closely associated with pathophysiological conditions, such as stroke, heart attack and septic shock. In an effort to identify target molecules of small compounds interfering with the signaling downstream of tumor necrosis factor-α (TNF-α), necrostatin-1 (Nec-1) was first identified to be a selective allosteric inhibitor of the death domain receptor-associated adaptor kinase, receptor interacting protein 1 (RIP1) in vitro. Since then, some novel scaffolds with selective and distinctive activity have been proposed. In this review, the significant advancement and state-of-art direction for the development of small molecules that can control programmed necrosis is discussed. Furthermore, the perspectives on novel strategies harnessing therapeutic targets identified thus far, are also discussed.
面对压倒性的外部刺激，细胞被迫以不同方式死亡。默认情况下，细胞易于发生凋亡，即通过激活半胱天冬酶级联反应的程序性细胞死亡。然而，如果参与执行凋亡的蛋白质之一发生基因损伤或受到化学抑制，或者如果凋亡机制在特定条件下（如缺血和微生物感染）不能正常运行，这个过程就会被阻断。为了解决这些问题，程序性细胞死亡的范式需要修正；因此，一种不同于凋亡的替代性细胞死亡形式——程序性坏死（通过不依赖半胱天冬酶的途径，称为坏死性凋亡）最近被采用。程序性坏死备受关注，因为它与诸如中风、心脏病发作和脓毒性休克等病理生理状况密切相关。为了鉴定干扰肿瘤坏死因子-α（TNF-α）下游信号传导的小分子的靶分子，坏死抑制因子-1（Nec-1）首先在体外被鉴定为死亡结构域受体相关衔接子激酶——受体相互作用蛋白1（RIP1）的选择性变构抑制剂。从那时起，已经提出了一些具有选择性和独特活性的新型支架。在这篇综述中，讨论了能够控制程序性坏死的小分子开发的重大进展和最新方向。此外，还讨论了利用迄今已确定的治疗靶点的新策略的前景。
