Cancer Center of Peking University Third Hospital, Beijing, China; Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China.
Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China.
EBioMedicine. 2024 Feb;100:104972. doi: 10.1016/j.ebiom.2024.104972. Epub 2024 Jan 19.
The importance of EZH2 as a key methyltransferase has been well documented theoretically. Practically, the first EZH2 inhibitor Tazemetostat (EPZ6438), was approved by FDA in 2020 and is used in clinic. However, for most solid tumors it is not as effective as desired and the scope of clinical indications is limited, suggesting that targeting its enzymatic activity may not be sufficient. Recent technologies focusing on the degradation of EZH2 protein have drawn attention due to their potential robust effects. This review focuses on the molecular mechanisms that regulate EZH2 protein stability via post-translational modifications (PTMs), mainly including ubiquitination, phosphorylation, and acetylation. In addition, we discuss recent advancements of multiple proteolysis targeting chimeras (PROTACs) strategies and the latest degraders that can downregulate EZH2 protein. We aim to highlight future directions to expand the application of novel EZH2 inhibitors by targeting both EZH2 enzymatic activity and protein stability.
EZH2 作为一种关键的甲基转移酶的重要性在理论上已有充分的文献记载。实际上，第一种 EZH2 抑制剂 Tazemetostat（EPZ6438）已于 2020 年获得 FDA 批准，并在临床上使用。然而，对于大多数实体瘤来说，其效果并不如预期的那样好，临床适应证的范围有限，这表明仅针对其酶活性可能还不够。由于其潜在的强大效果，最近专注于 EZH2 蛋白降解的技术引起了人们的关注。本文重点介绍了通过翻译后修饰（PTMs）调节 EZH2 蛋白稳定性的分子机制，主要包括泛素化、磷酸化和乙酰化。此外，我们还讨论了多种蛋白水解靶向嵌合体（PROTAC）策略和最新的降解剂的最新进展，这些降解剂可以下调 EZH2 蛋白。我们旨在强调通过靶向 EZH2 酶活性和蛋白稳定性来扩大新型 EZH2 抑制剂应用的未来方向。
