用于选择性蛋白质降解的前体PROTAC开发的最新进展。

Recent Advances in the Development of Pro-PROTAC for Selective Protein Degradation.

作者信息

Hakem Fady, Abdelwaly Ahmad, Alshaman Reem, Alattar Abdullah, Alanazi Fawaz E, Zaitone Sawsan A, Helal Mohamed A

机构信息

Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza 12587, Egypt.

Institute for Computational Molecular Science, Department of Chemistry, Temple University, Philadelphia, PA 19122, USA.

出版信息

Pharmaceutics. 2025 Sep 4;17(9):1160. doi: 10.3390/pharmaceutics17091160.

DOI:10.3390/pharmaceutics17091160

PMID:41012497

Abstract

PROTACs are trimeric small molecules consisting of a specific modulator of the target protein connected to a ligase-recruiting ligand via a suitably flexible linker. Ligase-recruiting ligands deliver ubiquitin ligases like E3 ligase to the Protein of Interest (POI). The vicinity of the POI-PROTAC-E3 ternary complex enables the E3 ligase to ubiquitinate the surface lysine residues of the POI. The Ubiquitin-Proteasome System (UPS) then degrades the POI. However, despite the considerable advances in the design of PROTACs targeting several types of enzymes and receptors, this strategy is still facing the challenges of precision target delivery and duration of action. In this review, we highlight the recent approaches for the development of PROTAC prodrugs or pro-PROTAC to control the delivery of PROTACs and achieve the required on-target exposure. This strategy may facilitate the application of the PROTAC technology and expand its clinical benefits.

摘要

蛋白水解靶向嵌合体（PROTACs）是三聚体小分子，由目标蛋白的特定调节剂通过适当的柔性接头连接到连接酶招募配体组成。连接酶招募配体将泛素连接酶（如E3连接酶）递送至目标蛋白（POI）。POI-PROTAC-E3三元复合物的形成使得E3连接酶能够将POI表面的赖氨酸残基泛素化。随后，泛素-蛋白酶体系统（UPS）降解POI。然而，尽管在设计针对多种类型酶和受体的PROTACs方面取得了相当大的进展，但该策略仍面临精准靶点递送和作用持续时间的挑战。在本综述中，我们重点介绍了开发PROTAC前药或前体PROTAC以控制PROTACs递送并实现所需靶点暴露的最新方法。该策略可能会促进PROTAC技术的应用并扩大其临床益处。