文章：

靶向蛋白降解用于癌症治疗

Targeted protein degradation for cancer therapy

原文发布日期：2025-04-25

DOI: 10.1038/s41568-025-00817-8

类型: Review Article

开放获取: 否

英文摘要：

Targeted protein degradation (TPD) aims at reprogramming the target specificity of the ubiquitin–proteasome system, the major cellular protein disposal machinery, to induce selective ubiquitination and degradation of therapeutically relevant proteins. Since its conception over 20 years ago, TPD has gained a lot of attention mainly due to improvements in the design of bifunctional proteolysis targeting chimeras (PROTACs) and understanding the mechanisms underlying molecular glue degraders. Today, PROTACs are on the verge of a first clinical approval and recent structural and mechanistic insights combined with technological leaps promise to unlock the rational design of protein degraders, following the lead of lenalidomide and related clinically approved analogues. At the same time, the TPD universe is expanding at a record speed with the discovery of novel modalities beyond molecular glue degraders and PROTACs. Here we review the recent progress in the field, focusing on newly discovered degrader modalities, the current state of clinical degrader candidates for cancer therapy and upcoming design approaches.

摘要翻译： 

靶向蛋白降解（TPD）旨在重编程泛素-蛋白酶体系统（细胞主要蛋白质处理机制）的靶标特异性，诱导治疗相关蛋白发生选择性泛素化与降解。自20余年前概念提出以来，TPPD主要得益于双功能蛋白水解靶向嵌合体（PROTAC）设计的优化及对分子胶降解剂作用机制认识的深化，获得了广泛关注。如今，PROTACs即将迎来首次临床批准，而近期在结构与机制层面的突破结合技术飞跃，有望在以来那度胺及相关临床获批类似物为先导的基础上，实现蛋白降解剂的理性设计。与此同时，随着分子胶降解剂和PROTAC之外新模式的发现，TPD领域正以空前速度扩展。本文回顾了该领域最新进展，重点阐述新发现的降解剂模式、癌症治疗临床候选降解剂的现状及新兴设计策略。

原文链接：

Targeted protein degradation for cancer therapy