TheDNA methyltransferases (DNMTs) found in mammals include DNMT1,DNMT3A, and DNMT3B and are attractive targets in cancer chemotherapy.DNMT1 was the first among the DNMTs to be characterized, and it isresponsible for maintaining DNA methylation patterns. A number ofDNMT inhibitors have been reported, but most of them are nucleosideanalogs that can lead to toxic side effects and lack specificity.By combining docking-based virtual screening with biochemical analyses,we identified a novel compound, DC_05. DC_05 is a non-nucleoside DNMT1inhibitor with low micromolar IC50values and significantselectivity toward other AdoMet-dependent protein methyltransferases.Through a process of similarity-based analog searching, compoundsDC_501 and DC_517 were found to be more potent than DC_05. These threepotent compounds significantly inhibited cancer cell proliferation.The structure–activity relationship (SAR) and binding modesof these inhibitors were also analyzed to assist in the future developmentof more potent and more specific DNMT1 inhibitors. [ABSTRACT FROM AUTHOR]