Targeted protein degradation (TPD) is emerging as a strategy to overcome the limitations of traditional small-molecule inhibitors. Proteolysis-targeting chimera (PROTAC) technology can be used to target proteins by hijacking the ubiquitin-proteasome system. Conceptually, PROTAC aims to target the “undruggable” majority of proteins in the human proteome. Through constant exploration and optimization of PROTACs and the exploitation of other TPD strategies over two decades, TPD has expanded from theoretical studies to clinical strategies, with practical applications in oncological, immunological, and other diseases. In this review, we introduce the mechanisms, features, and molecular targets of orthodox PROTACs and summarize the PROTAC drugs under study as cancer therapeutics in clinical trials. We also discuss PROTAC derivatives and other TPD strategies, such as lysosome-targeting chimeras, autophagy-targeting chimeras, and molecular glue strategies. Collectively, the studies summarized herein support the full potential of TPD in the biomedical industry.

靶向蛋白质降解 (TPD) 正在成为一种克服传统小分子抑制剂局限性的策略。蛋白水解靶向嵌合体 (PROTAC) 技术可用于通过劫持泛素-蛋白酶体系统来靶向蛋白质。从概念上讲，PROTAC 旨在针对人类蛋白质组中“不可药用”的大多数蛋白质。通过二十多年来对PROTACs的不断探索和优化以及其他TPD策略的开发，TPD已从理论研究扩展到临床策略，并在肿瘤学、免疫学等疾病中得到实际应用。在这篇综述中，我们介绍了正统 PROTAC 的机制、特征和分子靶点，并总结了正在研究的 PROTAC 药物作为临床试验中的癌症治疗药物。我们还讨论了 PROTAC 衍生物和其他 TPD 策略，例如溶酶体靶向嵌合体、自噬靶向嵌合体和分子胶策略。总的来说，本文总结的研究支持 TPD 在生物医学行业中的全部潜力。