Inhibitors of epigenetic writers such as DNA methyltransferases (DNMTs) are attractive compounds for epigenetic drug and probe discovery. There are many small molecules tested as inhibitors of DNMTs but, overall, they do not have potent enzymatic inhibition. Chemical companies are developing focused libraries for epigenetic targets to advance probe and drug discovery. Based on a knowledge-based approach, herein, we report the identification of two quinazoline-based derivatives identified in focused libraries with nanomolar inhibition of DNMT1 (30 and 81 nM), more potent than the positive control S-adenosylhomocysteine. The two compounds had low micromolar activity of DNMT3A and did not inhibit DNMT3B. The quinazolines reported in this work have low cell toxicity and are potent inhibitors of the epigenetic target writer G9a at the enzymatic and cellular levels. Molecular modeling helped rationalize the enzymatic inhibitory activity at the molecular level of the two compounds against DNMT1 and DNMT3A. The quinazoline-based compounds are attractive as novel potent inhibitors of DNMTs and as dual and selective epigenetic agents targeting two families of epigenetic writers.

Inhibitors of epigenetic writers such as DNA methyltransferases (DNMTs) are attractive compounds for epigenetic drug and probe discovery. To advance epigenetic probes and drug discovery, chemical companies are developing focused libraries for epigenetic targets. Based on a knowledge-based approach, herein we report the identification of two quinazoline-based derivatives identified in focused libraries with sub-micromolar inhibition of DNMT1 (30 and 81 nM), more potent than S-adenosylhomocysteine. Also, both compounds had a low micromolar affinity of DNMT3A and did not inhibit DNMT3B. The enzymatic inhibitory activity of DNMT1 and DNMT3A was rationalized with molecular modeling. The quinazolines reported in this work are known to have low cell toxicity and be potent inhibitors of the epigenetic target G9a. Therefore, the quinazoline-based compounds presented are attractive not only as novel potent inhibitors of DNMTs but also as dual and selective epigenetic agents targeting two families of epigenetic writers.