Structure–activity relationships of methyl-lysine reader antagonists

The interaction between methyl-lysine binding proteins and methylated histones plays a crucial role in the regulation of gene expression. Herein we describe the development of structure–activity relationships (SAR) surrounding UNC669, the first reported small molecule ligand for a methyl-lysine binding domain, using multiple assay formats. These studies revealed the key features required for successful inhibition of the L3MBTL1-methylated histone protein-protein interaction, while the selectivity of designed compounds against a panel of related methyl-lysine readers was also evaluated. Additionally, an optimized compound was demonstrated to successfully inhibit the recognition of H4K20me1 by L3MBTL1 in the context of an affinity pull down assay.