Epigenetic reader chromodomain as a potential therapeutic target

Abstract

Epigenetic mechanisms involve cooperative actions of enzymes that produce or remove post-translational modifications in histones and ‘readers’, the protein domains that bind these modifications. Methylation of lysine residues represents one of the most common modifications and is recognized by a family of chromodomains. Chromodomain containing proteins are implicated in transcriptional regulation and chromatin remodeling, and aberrant functions of these proteins are linked to human diseases, such as cancer, neurodegenerative disorders and developmental abnormalities. In this work, we review biological and pathological activities of chromodomains, highlighting their potential as prognostic biomarkers and their attractiveness as therapeutic targets. In the past few years, significant progress has been made in the development of chromodomain inhibitors, however sequence similarity within this family of readers presents challenges in designing selective probes. We describe recent advances and new strategies that are employed to overcome these challenges, including structure-based drug design, high-throughput screening, the use of peptide and DNA encoded libraries, and summarize research underscoring the benefit of targeting chromodomains to combat diseases.