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、健康的环境是必不可少的。然而，当天然蛋白质稳态机制因过度负荷的失调蛋白质而不堪重负时，它们的积累会导致疾病的发生和进展。最近，异双功能分子（即蛋白水解靶向嵌合体（PROTACs））对这些致病蛋白的诱导降解正在成为一种潜在的治疗方式。在 PROTAC 概念提出后的 20 年中，还探索了几种额外的靶向蛋白质降解 (TPD) 策略来靶向以前无法成药的蛋白质，例如转录因子。在这篇评论中，我们讨论了 TPD 领域的进展和演变，