Protein homeostasis, or “proteostasis,” is indispensable for a balanced, healthy environment within the cell. However, when natural proteostasis mechanisms are overwhelmed from excessive loads of dysregulated proteins, their accumulation can lead to disease initiation and progression. Recently, the induced degradation of such disease-causing proteins by heterobifunctional molecules, i.e., PROteolysis TArgeting Chimeras (PROTACs), is emerging as a potential therapeutic modality. In the 2 decades since the PROTAC concept was proposed, several additional Targeted Protein Degradation (TPD) strategies have also been explored to target previously undruggable proteins, such as transcription factors. In this review, we discuss the progress and evolution of the TPD field, the breadth of the proteins targeted by PROTACs and the biological effects of their degradation.

蛋白质稳态或“蛋白质稳态”对于细胞内平衡、健康的环境是不可或缺的。然而，当天然蛋白质稳态机制因过量的失调蛋白质而被淹没时，它们的积累可能导致疾病的发生和进展。最近，通过异双功能分子（即蛋白水解靶向嵌合体（PROTAC））诱导降解此类致病蛋白，正在成为一种潜在的治疗方式。自 PROTAC 概念提出以来的 20 年间，人们还探索了几种额外的靶向蛋白质降解 (TPD) 策略，以靶向以前不可成药的蛋白质，例如转录因子。在这篇综述中，我们讨论了 TPD 领域的进展和演变、PROTAC 靶向蛋白质的广度及其降解的生物学效应。