Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, UK.
SLAS Discov. 2021 Apr;26(4):484-502. doi: 10.1177/2472555220965528. Epub 2020 Nov 3.
Bifunctional degrader molecules, also called proteolysis-targeting chimeras (PROTACs), are a new modality of chemical tools and potential therapeutics to understand and treat human disease. A required PROTAC component is a ligand binding to an E3 ubiquitin ligase, which is then joined to another ligand binding to a protein to be degraded via the ubiquitin-proteasome system. The advent of nonpeptidic small-molecule E3 ligase ligands, notably for von Hippel-Lindau (VHL) and cereblon (CRBN), revolutionized the field and ushered in the design of drug-like PROTACs with potent and selective degradation activity. A first wave of PROTAC drugs are now undergoing clinical development in cancer, and the field is seeking to extend the repertoire of chemistries that allow hijacking new E3 ligases to improve the scope of targeted protein degradation.Here, we briefly review how traditional E3 ligase ligands were discovered, and then outline approaches and ligands that have been recently used to discover new E3 ligases for PROTACs. We will then take an outlook at current and future strategies undertaken that invoke either target-based screening or phenotypic-based approaches, including the use of DNA-encoded libraries (DELs), display technologies and cyclic peptides, smaller molecular glue degraders, and covalent warhead ligands. These approaches are ripe for expanding the chemical space of PROTACs and usher in the advent of other emerging bifunctional modalities of proximity-based pharmacology.
双功能降解剂分子，也称为蛋白水解靶向嵌合体（PROTACs），是一种新的化学工具和潜在治疗方法，可以用于理解和治疗人类疾病。PROTAC 的一个必需组成部分是与 E3 泛素连接酶结合的配体，然后与另一个配体结合，通过泛素-蛋白酶体系统将靶蛋白降解。非肽小分子 E3 连接酶配体的出现，特别是针对 von Hippel-Lindau（VHL）和 cereblon（CRBN）的配体，彻底改变了这个领域，并推动了具有强大和选择性降解活性的类似药物 PROTAC 的设计。第一批 PROTAC 药物现在正在癌症的临床开发中，该领域正在寻求扩展允许劫持新 E3 连接酶的化学物质库，以扩大靶向蛋白降解的范围。在这里，我们简要回顾了传统 E3 连接酶配体的发现方式，然后概述了最近用于发现用于 PROTAC 的新 E3 连接酶的方法和配体。然后，我们将着眼于当前和未来的策略，这些策略既包括基于靶标的筛选，也包括基于表型的方法，包括使用 DNA 编码文库（DEL）、显示技术和环状肽、更小的分子胶降解剂以及共价弹头配体。这些方法为扩大 PROTAC 的化学空间并迎来其他新兴的基于邻近性的药理学双功能模式铺平了道路。
