School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.
Curr Top Med Chem. 2019;19(12):1059-1069. doi: 10.2174/1568026619666190311110646.
Neddylation is an important post-translational modification of proteins, in which a NEDD8 (neural-precursor-cell-expressed developmentally down-regulated 8) is covalently introduced onto the substrate proteins to regulate their functions and homeostasis. As neddylation is frequently up-regulated in various cancers, its interference was proposed as a promising therapy of related diseases.
The recent advances in developing neddylation interfering agents were summarized to provide an overview of current achievements and perspectives for future development.
Reports on neddylation interfering agents were acquired from Pubmed as well as the EPO and clinicaltrials.gov websites, which were subsequently analyzed and summarized according to targets, chemical structures and biological activities.
Neddylation as a sophisticated procedure comprises proteolytic processing of NEDD8 precursor, deploying conjugating enzymes E1 (NAE), E2 (UBE2M and UBE2F) and various E3, as well as translocating NEDD8 along these conjugating enzymes sequentially and finally to substrate proteins. Among these nodes, NAE, UBE2M and the interaction between UBE2M-DCN1 have been targeted by small molecules, metal complexes, peptides and RNAi. A NAE inhibitor pevonedistat (MLN4924) is currently under evaluation in clinical trials for the treatment of various cancers.
With multiple inhibitory approaches of neddylation being introduced, the development of neddylation interference as a novel cancer therapy is significantly boosted recently, although its efficacy and the best way to achieve that are still to be demonstrated in clinical trials.
泛素化是蛋白质的一种重要的翻译后修饰，在此过程中，一个 NEDD8（神经前体细胞表达的发育下调 8）共价连接到底物蛋白上，以调节它们的功能和动态平衡。由于泛素化在各种癌症中经常上调，因此干扰泛素化被认为是治疗相关疾病的一种有前途的方法。
总结了近年来开发泛素化干扰剂的最新进展，为未来的发展提供了当前成就和展望的概述。
从 Pubmed 以及 EPO 和 clinicaltrials.gov 网站上获取泛素化干扰剂的报告，根据靶点、化学结构和生物学活性对这些报告进行分析和总结。
泛素化作为一个复杂的过程，包括 NEDD8 前体的蛋白水解加工，利用 E1（NAE）、E2（UBE2M 和 UBE2F）和各种 E3 连接酶，以及沿着这些连接酶将 NEDD8 转移到底物蛋白上。在这些节点中，NAE、UBE2M 和 UBE2M-DCN1 之间的相互作用已被小分子、金属配合物、肽和 RNAi 靶向。一种 NAE 抑制剂 pevonedistat（MLN4924）目前正在临床试验中评估用于治疗各种癌症。
随着泛素化抑制作用的多种抑制方法的引入，泛素化干扰作为一种新型癌症治疗方法的发展最近得到了显著推动，尽管其疗效和最佳实现方式仍需在临床试验中证明。
