PROTACs in cancer therapy: targeted degradation of GPX4, PARP and epigenetic regulators

The degradation of overexpressed proteins has emerged as a promising strategy for halting disease progression, particularly in cancer. Traditional small-molecule drugs often face limitations in the elimination of pathogenic proteins, leading to the development of targeted protein degradation (TPD) approaches. A prominent strategy for TPD is the proteolysis targeting chimaera (PROTAC) which harnesses the ubiquitin proteasome system, the cell's innate degradation machinery, to degrade proteins of interest (POIs). In this review, we will focus on the design and synthetic strategies that led the advancements of PROTACs as a cancer therapy for the targeted degradation of poly ADP-ribose polymerases (PARPs), glutathione peroxidase 4 (GPX4) and epigenetic regulators. We also aim to address the prevailing challenges in PROTAC development and clinical translation, namely target diversification, oral bioavailability, stability, degradation efficiency, and optimising multivalent binding.