异双功能蛋白水解酶分解物，如蛋白质分解靶向嵌合物（PROTAC）蛋白水解酶分解物，构成了一种新颖的治疗方式，利用细胞的天然蛋白质降解机制-泛素蛋白酶体系统选择性地靶向致病性蛋白用于消除。蛋白质分解物与传统用于癌症治疗的小分子抑制剂相比，有几个潜在的优势，包括事件驱动（而不是占位驱动）药理学，这允许亚计量药物浓度用于活性，它们的能力反复作用并靶向多个感兴趣蛋白，以及靶向以前被认为无法抑制的非酶蛋白的潜力。随着蛋白质分解物设计的许多创新和在动物模型中的严格评价，蛋白质分解物于2019年进入了临床测试。目前，有18种蛋白质分解物正在I期或I / II期临床试验中，涉及患有不同肿瘤类型的患者，其中一种的III期试验于2022年启动。来自这些研究的第一批安全性，功效和药代动力学数据正在现实中出现，虽然还需要更多证据，但蛋白质降解剂正在显示出作为癌症治疗药物的有希望的活性。本文回顾了蛋白质降解物发展的进展，支持它们进入临床研究的临床前研究，患者蛋白质降解物的可用数据和这种新型药物的未来方向。©2023. Springer Nature Limited.

Heterobifunctional protein degraders, such as PROteolysis TArgeting Chimera (PROTAC) protein degraders, constitute a novel therapeutic modality that harnesses the cell's natural protein-degradation machinery - that is, the ubiquitin-proteasome system - to selectively target proteins involved in disease pathogenesis for elimination. Protein degraders have several potential advantages over small-molecule inhibitors that have traditionally been used for cancer treatment, including their event-driven (rather than occupancy-driven) pharmacology, which permits sub-stoichiometric drug concentrations for activity, their capacity to act iteratively and target multiple copies of a protein of interest, and their potential to target nonenzymatic proteins that were previously considered 'undruggable'. Following numerous innovations in protein degrader design and rigorous evaluation in preclinical models, protein degraders entered clinical testing in 2019. Currently, 18 protein degraders are in phase I or phase I/II clinical trials that involve patients with various tumour types, with a phase III trial of one initiated in 2022. The first safety, efficacy and pharmacokinetic data from these studies are now materializing and, although considerably more evidence is needed, protein degraders are showing promising activity as cancer therapies. Herein, we review advances in protein degrader development, the preclinical research that supported their entry into clinical studies, the available data for protein degraders in patients and future directions for this new class of drugs.© 2023. Springer Nature Limited.