Targeted protein degradation (TPD) has emerged as an exciting new era in chemical biology and drug discovery. PROteolysis TArgeting Chimera (PROTAC) technology targets cellular proteins for degradation by co-opting the ubiquitin-proteasome system. Over the last 5 years, numerous studies have expanded our understanding of the unique mode of action and advantages of PROTACs, which has in turn spurred interest in both academia and industry to explore PROTACs as a novel therapeutic strategy. In this review, we first highlight the key advantages of PROTACs and then discuss the spatiotemporal regulation of protein degradation. Next, we explore current chemically tractable E3 ligases focusing on expanding the existing repertoire with novel E3 ligases to uncover the full potential of TPD. Collectively, these studies are guiding the development of the PROTAC technology as it emerges as a new modality in precision medicine.

靶向蛋白质降解 (TPD) 已成为化学生物学和药物发现的一个激动人心的新时代。PROteolysis Targeting Chimera (PROTAC) 技术通过选择泛素-蛋白酶体系统来靶向降解细胞蛋白。在过去的 5 年中，大量研究扩大了我们对 PROTAC 独特作用模式和优势的理解，这反过来又激发了学术界和工业界对探索 PROTAC 作为一种新型治疗策略的兴趣。在这篇综述中，我们首先强调了 PROTAC 的主要优势，然后讨论了蛋白质降解的时空调控。接下来，我们探索当前化学上易于处理的 E3 连接酶，重点是用新的 E3 连接酶扩展现有的库，以揭示 TPD 的全部潜力。集体，