Targeted protein degradation (TPD) using proteolysis targeting chimeras (PROTACs) and molecular glue degraders has arisen as a powerful therapeutic modality for eliminating disease-causing proteins from cells. PROTACs and molecular glue degraders employ heterobifunctional or monovalent small molecules, respectively, to chemically induce the proximity of target proteins with E3 ubiquitin ligases to ubiquitinate and degrade specific proteins via the proteasome. Whereas TPD is an attractive therapeutic strategy for expanding the druggable proteome, only a relatively small number of E3 ligases out of the >600 E3 ligases encoded by the human genome have been exploited by small molecules for TPD applications. Here we review the existing E3 ligases that have thus far been successfully exploited for TPD and discuss chemoproteomics-enabled covalent screening strategies for discovering new E3 ligase recruiters. We also provide a chemoproteomic map of reactive cysteines within hundreds of E3 ligases that may represent potential ligandable sites that can be pharmacologically interrogated to uncover additional E3 ligase recruiters.

中文翻译：

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E3 连接酶在靶向蛋白质降解应用中的配体能力

使用蛋白水解靶向嵌合体 (PROTAC) 和分子胶降解剂的靶向蛋白降解 (TPD) 已成为消除细胞中致病蛋白的强大治疗方式。PROTAC 和分子胶降解剂分别采用异双功能或单价小分子，以化学方式诱导靶蛋白与 E3 泛素连接酶的接近，从而通过蛋白酶体泛素化和降解特定蛋白质。尽管 TPD 是扩展药物蛋白质组的一种有吸引力的治疗策略，但在人类基因组编码的 >600 种 E3 连接酶中，只有相对少量的 E3 连接酶被小分子用于 TPD 应用。在这里，我们回顾了迄今为止已成功用于 TPD 的现有 E3 连接酶，并讨论了化学蛋白质组学启用的共价筛选策略，以发现新的 E3 连接酶招募者。我们还提供了数百个 E3 连接酶中反应性半胱氨酸的化学蛋白质组学图谱，这些图谱可能代表潜在的配体位点，可以通过药理学研究来发现更多的 E3 连接酶招募者。