Selective Small‐Molecule Inhibitors of Protein Methyltransferases

Epigenetic regulation of gene expression depends on the state of chromatin, which can be modified in a variety of ways, including DNA methylation, nucleosome remodeling histone variants, and posttranslational modifications (PTMs) of histones. Protein methyltransferases (PMTs) are implicated in various cancers and numerous other diseases, and the discovery of selective small-molecule inhibitors of PMTs has become a very active research area. This chapter highlight the progress made in the discovery of PMT inhibitors in the last 15 years. PMTs are classified based on the residues they modify: protein lysine methyltransferases (PKMTs) and protein arginine methyltransferases (PRMTs). The lysine residues can be mono-, di-, and/or trimethylated by PKMTs, and the arginine residues can only be mono- and/or dimethylated by PRMTs. Protein arginine methylation is another significant and widely observed PTM in eukaryotic cells. Every methylation of arginine prevents a potential hydrogen bond, creating steric bulkiness and increasing hydrophobicity.