蛋白降解靶向嵌合体临床前及临床研究进展

Advances in the preclinical and clinical research of proteolysis targeting chimera

摘要:

蛋白降解靶向嵌合体(proteolysis targeting chimera, PROTAC)是一种可以同时结合E3连接酶和靶蛋白的异双功能小分子，能够借助泛素-蛋白酶体系统特异性降解靶蛋白。目前PROTAC药物大多处于临床试验阶段，配体主要为非共价化合物，具有克服耐药性、降解“不可用药”靶蛋白的优势，但非共价配体会使PROTAC产生钩效应(hook effect)，影响药效发挥。而共价配体凭借自身优势，可以避免该现象的发生，对于PROTAC的发展具有极大的帮助。本文总结了临床前及临床研究阶段，PROTAC分子在核内蛋白、跨膜蛋白和胞浆蛋白3种蛋白靶点中的应用，并以此为基础进行了讨论与展望，以期为今后PROTAC的发展提供一定的研究思路和参考。

Abstract:

Proteolysis targeting chimera (PROTAC) refers to heterobifunctional small molecules that can simultaneously bind an E3 ubiquitin ligase and a target protein, enabling specific degradation of the target protein with the aid of the ubiquitin proteasome system. At present, most PROTAC drugs are in the clinical trial stage, and the ligands are mainly non-covalent compounds. PROTAC drugs have the advantage of overcoming drug resistance and degrading “undruggable” target proteins, but non-covalent ligands could lead to the hook effect that undermines drug efficacy. With its own advantages, covalent ligands can avoid the occurrence of this phenomenon, which is of great help to the development of PROTAC. This review summarizes the progress in preclinical and clinical research and application of PROTAC molecules targeting three different classes of protein targets, including intranuclear, transmembrane, and cytosolic proteins. We also offer perspective discussions to provide research ideas and references for the future development of PROTAC.