Structureactivity relationships of methyl-lysine reader antagonistsThis article is part of a MedChemComm web theme issue on epigenetics.Electronic supplementary information (ESI) available: In vitro assay conditions, representative AlphaScreen and ITC binding curves, experimental procedures including spectra for all final compounds. See DOI: 10.1039/c1md00195g

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 structureactivity 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. The structureactivity relationships for small molecule antagonists of the Malignant Brain Tumor (MBT) domain family of methyl-lysine readers are described and activity demonstrated in histone peptide pull-down assays.