文章：

推进靶向蛋白降解用于癌症治疗

Advancing targeted protein degradation for cancer therapy

原文发布日期：2021-06-15

DOI: 10.1038/s41568-021-00365-x

类型: Review Article

开放获取: 否

英文摘要：

The human proteome contains approximately 20,000 proteins, and it is estimated that more than 600 of them are functionally important for various types of cancers, including nearly 400 non-enzyme proteins that are challenging to target by traditional occupancy-driven pharmacology. Recent advances in the development of small-molecule degraders, including molecular glues and heterobifunctional degraders such as proteolysis-targeting chimeras (PROTACs), have made it possible to target many proteins that were previously considered undruggable. In particular, PROTACs form a ternary complex with a hijacked E3 ubiquitin ligase and a target protein, leading to polyubiquitination and degradation of the target protein. The broad applicability of this approach is facilitated by the flexibility of individual E3 ligases to recognize different substrates. The vast majority of the approximately 600 human E3 ligases have not been explored, thus presenting enormous opportunities to develop degraders that target oncoproteins with tissue, tumour and subcellular selectivity. In this Review, we first discuss the molecular basis of targeted protein degradation. We then offer a comprehensive account of the most promising degraders in development as cancer therapies to date. Lastly, we provide an overview of opportunities and challenges in this exciting field.

摘要翻译： 

人类蛋白质组包含约20,000种蛋白质，其中估计有600多种对各类癌症具有重要功能意义，包括近400种难以通过传统占位驱动药理学靶向的非酶蛋白。小分子降解剂（包括分子胶和异双功能降解剂，如蛋白水解靶向嵌合体PROTACs）开发的最新进展，使得靶向许多先前被认为不可成药的蛋白质成为可能。特别是PROTACs能与被劫持的E3泛素连接酶及靶蛋白形成三元复合物，导致靶蛋白发生多聚泛素化并被降解。该方法具有广泛适用性，这得益于个体E3连接酶识别不同底物的灵活性。目前人类约600种E3连接酶中绝大多数尚未被探索，因此为开发具有组织、肿瘤和亚细胞选择性的靶向致癌蛋白降解剂提供了巨大机遇。本文首先探讨靶向蛋白降解的分子基础，随后全面总结目前最具前景的癌症治疗降解剂研发进展，最后概述这一激动人心领域面临的机遇与挑战。

原文链接：

Advancing targeted protein degradation for cancer therapy