Improved methods for targeting epigenetic reader domains of acetylated and methylated lysine

Abstract

Responsible for interpreting histone post-translational modifications, epigenetic reader proteins have emerged as novel therapeutic targets for a wide range of diseases. Chemical probes have been critical in enabling target validation studies and have led to translational advances in cancer and inflammation-related pathologies. Here, we present the most recently reported probes of reader proteins that recognize acylated and methylated lysine. We will discuss challenges associated with achieving potent antagonism of reader domains and review ongoing efforts to overcome these hurdles, focusing on targeting strategies including the use of peptidomimetic ligands, allosteric modulators, and protein degraders.

Keywords: Acylated and methylated lysine; Allosteric modulators; Bromodomains; Chemical probes; Chromatin regulatory factors; Epigenetic reader proteins; Histone post-translational modifications; Peptidomimetic ligands; Protein degraders; Small-molecule antagonists.