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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]

Alterations of fibroblast growth factor receptors (FGFRs) play key roles in numerous cancer progression and development, which makes FGFRs attractive targets in the cancer therapy. In the present study, based on a newly devised FGFR target-specific scoring function, a novel FGFR inhibitor hit was identified through virtual screening. Hit-to-lead optimization was then performed by integrating molecular docking and site-of-metabolism predictions with an array of in vitro evaluations and X-ray cocrystal structure determination, leading to a covalent FGFR inhibitor 15 , which showed a highly selective and potent FGFR inhibition profile. Pharmacokinetic assessment, protein kinase profiling, and hERG inhibition evaluation were also conducted, and they confirmed the value of 15 as a lead for further investigation. Overall, this study exemplifies the importance of the integrative use of computational methods and experimental techniques in drug discovery.