Chemically induced degradation of epigenetic targets

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional small molecules that induce the ternary complex formation between a protein-of-interest (POI) and an E3 ligase, leading to targeted polyubiquitination and degradation of the POI. Particularly, PROTACs have the distinct advantage of targeting both canonical and noncanonical functions of epigenetic targets over traditional inhibitors, which typically target canonical functions only, resulting in greater therapeutic efficacy. In this review, we methodically analyze published PROTAC degraders of epigenetic writer, reader, and eraser proteins and their in vitro and in vivo effects. We highlight the mechanism of action of these degraders and their advantages in targeting both canonical and noncanonical functions of epigenetic targets in the context of cancer treatment. Furthermore, we present a future outlook for this exciting field. Overall, pharmacological degradation of epigenetic targets has emerged as an effective and attractive strategy to thwart cancer progression and growth.

Automated summary

Proteolysis-targeting chimeras (PROTACs) are small molecules that induce targeted degradation of proteins by forming ternary complexes with E3 ligases. They have the advantage of targeting both canonical and noncanonical functions of epigenetic targets, resulting in greater therapeutic efficacy. This review analyzes published PROTAC degraders of epigenetic writer, reader, and eraser proteins and discusses their mechanism of action and advantages in cancer treatment. Overall, pharmacological degradation of epigenetic targets has emerged as an effective strategy against cancer.