From Inhibition to Degradation: Proteolysis-Targeting Chimeras for Epigenetic Enzymes in Modern Drug Discovery

Abstract Epigenetic enzymes are important therapeutic targets in several diseases, including cancer. This review summarizes recent studies on proteolysis-targeting chimeras (PROTACs) for epigenetic enzymes, with a focus on HDAC8, G9a/GLP, and KDM5. These case studies highlight the transition from conventional inhibition to targeted degradation and demonstrate the potential of degraders to modulate both catalytic and non-catalytic functions. We also discuss current challenges and future perspectives in the development of selective epigenetic degraders.