The human proteome contains approximately 20,000 proteins, and it is estimated that more than 600 of them are functionally important for various types of cancers, including nearly 400 non-enzyme proteins that are challenging to target by traditional occupancy-driven pharmacology. Recent advances in the development of small-molecule degraders, including molecular glues and heterobifunctional degraders such as proteolysis-targeting chimeras (PROTACs), have made it possible to target many proteins that were previously considered undruggable. In particular, PROTACs form a ternary complex with a hijacked E3 ubiquitin ligase and a target protein, leading to polyubiquitination and degradation of the target protein. The broad applicability of this approach is facilitated by the flexibility of individual E3 ligases to recognize different substrates. The vast majority of the approximately 600 human E3 ligases have not been explored, thus presenting enormous opportunities to develop degraders that target oncoproteins with tissue, tumour and subcellular selectivity. In this Review, we first discuss the molecular basis of targeted protein degradation. We then offer a comprehensive account of the most promising degraders in development as cancer therapies to date. Lastly, we provide an overview of opportunities and challenges in this exciting field.

人类蛋白质组包含大约 20,000 种蛋白质，据估计其中超过 600 种蛋白质对各种类型的癌症具有重要的功能，包括近 400 种非酶蛋白，传统的占位驱动药理学难以靶向这些蛋白质。小分子降解剂的最新进展，包括分子胶和异双功能降解剂，如蛋白水解靶向嵌合体 (PROTAC)，使得靶向许多以前被认为不可药物化的蛋白质成为可能。特别是，PROTAC 与劫持的 E3 泛素连接酶和靶蛋白形成三元复合物，导致靶蛋白的多泛素化和降解。单个 E3 连接酶识别不同底物的灵活性促进了这种方法的广泛适用性。大约 600 种人类 E3 连接酶中的绝大多数尚未被探索，因此为开发具有组织、肿瘤和亚细胞选择性的靶向癌蛋白的降解剂提供了巨大的机会。在这篇综述中，我们首先讨论了靶向蛋白质降解的分子基础。然后，我们全面介绍了迄今为止作为癌症疗法开发的最有前途的降解剂。最后，我们概述了这个令人兴奋的领域中的机遇和挑战。然后，我们全面介绍了迄今为止作为癌症疗法开发的最有前途的降解剂。最后，我们概述了这个令人兴奋的领域中的机遇和挑战。然后，我们全面介绍了迄今为止作为癌症疗法开发的最有前途的降解剂。最后，我们概述了这个令人兴奋的领域中的机遇和挑战。