Discovery of novel 4-aminobenzamide derivatives as small molecule CBX2 inhibitors.

CBX2 protein plays an important role in methyl-lysine recognition involved in epigenetic regulation. In contrast to CBX7 modulators, there are few reported CBX2 inhibitors, most of which are peptidergic molecules. This fact encouraged us to search non-peptidic small molecule CBX2 inhibitors with sufficient cell permeability by in silico screening followed by synthetic evolution. In virtual screening, we identified a 4-aminobenzamide scaffold with high in silico score and Nano BRET activities. Based on several in silico hit compounds, we synthesized a series of 4-aminobenzamide derivatives and tested their Nano BRET activities. Among them, compound 37 showed moderate CBX2 inhibitory activity with an IC50 value of 9.6 μM, a potential lead compound. This is a first small molecule CBX2 inhibitor identified as a result of SAR studies and lead optimization by medicinal chemistry.