A novel class of selective non-nucleoside inhibitors of human DNA methyltransferase 3A

Screening of a small chemical library (Medicines for Malaria Venture Pathogen Box) identified two structurally related pyrazolone (inhibitor 1) and pyridazine 2) DNMT3A inhibitors with low micromolar inhibition constants. The uncompetitive mixed type patterns DNA AdoMet suggest these molecules act through an allosteric mechanism, thus are unlikely to bind the enzyme’s active site. Unlike clinically used mechanism based DNMT such as decitabine or azacitidine that via enzyme site, described here could lead development more selective drugs. Both show promising selectivity in comparison DNMT1 bacterial cytosine methyltransferases. With further study, this form basis preferential targeting de novo methylation over maintenance methylation.