PT  - JOURNAL ARTICLE
AU  - K. Eurídice Juárez-Mercado
AU  - Fernando D. Prieto-Martínez
AU  - Norberto Sánchez-Cruz
AU  - Andrea Peña-Castillo
AU  - Diego Prada-Gracia
AU  - José L. Medina-Franco
TI  - DNA Methyltransferase Inhibitors with Novel Chemical Scaffolds
AID  - 10.1101/2020.10.13.337709
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.10.13.337709
4099  - http://biorxiv.org/content/early/2020/10/14/2020.10.13.337709.short
4100  - http://biorxiv.org/content/early/2020/10/14/2020.10.13.337709.full
AB  - 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 StatementThe authors have declared no competing interest.3H-SAMTritium-labeled AdoMetDNMTDNA methyltransferaseECIFExtended Connectivity Interactions FeaturesFDAFood and Drug Administration3H-SAMtritium-labeled AdoMetHDACHistone deacetylase inhibitorIC50Half maximal inhibitory concentrationMOEMolecular Operating EnvironmentPDBProtein Data BankSAHS-adenosyl-L-homocysteineSAMS-adenosyl-L-methionine.