蛋白neddylation是一种翻译后修饰,可通过三步酶促级联将泛素样蛋白NEDD8转移到目标底物的赖氨酸残基。neddylation最著名的底物是cullin家族蛋白,它们是Cullin-RINGE3泛素连接酶(CRL)的核心成分。鉴于CRL活性需要cullinneddylation,CRLs控制着各种关键信号蛋白的翻转,并且在癌症中通常异常激活,靶向neddylation成为发现新型抗癌疗法的有希望的方法。在过去的十年里,从临床前靶标验证,我们见证了蛋白质Neddylation领域的重大进展,药物筛选,然后是Neddylation抑制剂的临床试验。在这次审查中,我们首先简要介绍了蛋白质neddylation的性质和neddylation级联的调控,然后是所有报道的奈德酶化学抑制剂的总结。然后,我们讨论了Neddylation级联中蛋白质-蛋白质相互作用的基于结构的靶向,最后是发现新的neddylation抑制剂的可用方法。这次审查将提供一个有重点的,关于Neddylation抑制剂的发现工作的最新而又全面的概述。
Protein neddylation is a post-translational modification which transfers the ubiquitin-like protein NEDD8 to a lysine residue of the target substrate through a three-step enzymatic cascade. The best-known substrates of neddylation are cullin family proteins, which are the core component of Cullin-RING E3 ubiquitin ligases (CRLs). Given that cullin neddylation is required for CRL activity, and CRLs control the turn-over of a variety of key signal proteins and are often abnormally activated in cancers, targeting neddylation becomes a promising approach for discovery of novel anti-cancer therapeutics. In the past decade, we have witnessed significant progress in the field of protein neddylation from preclinical target validation, to drug screening, then to the clinical trials of neddylation inhibitors. In this review, we first briefly introduced the nature of protein neddylation and the regulation of neddylation cascade, followed by a summary of all reported chemical inhibitors of neddylation enzymes. We then discussed the structure-based targeting of protein-protein interaction in neddylation cascade, and finally the available approaches for the discovery of new neddylation inhibitors. This review will provide a focused, up-to-date and yet comprehensive overview on the discovery effort of neddylation inhibitors.