DNA Methyltransferase Inhibitors with Novel Chemical Scaffolds

Inhibitors of DNA methyltransferases (DNMTs) are attractive compounds for epigenetic drug discovery. They are also chemical tools to understand the biochemistry of epigenetic processes. Herein, we report five distinct inhibitors of DNMT1 characterized in enzymatic inhibition assays that did not show activity with DNMT3B. It was concluded that the dietary component theaflavin is an inhibitor of DNMT1. Two additional novel inhibitors of DNMT1 are the approved drugs glyburide and panobinostat. The DNMT1 enzymatic inhibitory activity of panobinostat, a known pan inhibitor of histone deacetylases, agrees with experimental reports of its ability to reduce DNMT1 activity in liver cancer cell lines. Molecular docking of the active compounds with DNMT1, and re-scoring with the recently developed Extended Connectivity Interaction Features approach, had an excellent agreement between the experimental IC50 values and docking scores. ### Competing Interest Statement The authors have declared no competing interest. * 3H-SAM : Tritium-labeled AdoMet DNMT : DNA methyltransferase ECIF : Extended Connectivity Interactions Features FDA : Food and Drug Administration 3H-SAM : tritium-labeled AdoMet HDAC : Histone deacetylase inhibitor IC50 : Half maximal inhibitory concentration MOE : Molecular Operating Environment PDB : Protein Data Bank SAH : S -adenosyl- L -homocysteine SAM : S -adenosyl-L-methionine.