PROTACs Targeting Epigenetic Proteins.

Abstract

Epigenetics, a field that investigates alterations in gene function that can be inherited without changes in DNA sequence, encompasses molecular pathways such as histone variants, posttranslational modifications of amino acids, and covalent modifications of DNA bases. These pathways modulate the transformation of genotypes into specific phenotypes. Epigenetics plays a substantial role in cell growth, development, and differentiation by dynamically regulating gene transcription and ensuring genomic stability. This regulation is carried out by three key players: writers, readers, and erasers. In recent years, epigenetic proteins have played a crucial role in epigenetic regulation and have gradually become important targets in drug research and development. Targeted therapy is an essential strategy; however, the effectiveness of targeted drugs is often limited by drug resistance, posing a significant dilemma in clinical practice. Targeted protein degradation technologies, including proteolysis-targeting chimeras (PROTACs), have great potential in overcoming drug resistance and targeting undruggable targets. These areas of research are gaining increasing attention to various epigenetic related disease. In this review, we have provided a summary of the recently developed degraders targeting epigenetic readers, writers, and erasers. Additionally, we have outlined new applications for epigenetic protein degraders. Finally, we have addressed several unresolved challenges within the PROTAC field and offered potential solutions from our perspective. As the field continues to advance, the integration of these innovative methodologies holds great promise for addressing the challenges associated with PROTAC development.