Targeted protein degradation: A promise for undruggable proteins

Abstract

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.