title: Identification of novel bacterial M.SssI DNA methyltransferase inhibitors.
abstract: DNA methylation is an important epigenetic regulator of gene expression. Abnormalities in DNA methylation patterns have been associated with various developmental and proliferative diseases, particularly cancer. Targeting DNA methyltransferases (DNMTs) represents a promising strategy for the treatment of such diseases. Current DNMT inhibitors suffer important drawbacks with respect to their efficacy, specificity, and toxicity. In this study, we have set up a robust in vitro bacterial M.SssI DNMT activity assay to systematically screen a collection of 26 240 compounds that were predicted to compete with the S-adenosyl-L-methionine (SAM) substrate of DNMT. This resulted in the identification of a novel set of structurally distinct inhibitors of M.SssI DNMT activity. Although molecular docking studies using an M.SssI homology model suggest that these compounds might compete with SAM binding, mode of activity (MoA) assays are still needed to confirm this hypothesis. Our set of novel M.SssI DNMT inhibitors, once confirmed in an orthogonal DNMT assay, may thus serve as a starting point to identify and characterize suitable lead candidates for further drug optimization.
authors.affiliation: Department of Cell and Applied Biology, Radboud University Nijmegen, Nijmegen, 6525 AJ, Netherlands. m.hupkes@science.ru.nl
authors.forename: Marlinda
authors.initials: M
authors.lastname: Hupkes
authors.forename: Rita
authors.initials: R
authors.lastname: Azevedo
authors.forename: Hans
authors.initials: H
authors.lastname: Jansen
authors.forename: Everardus J
authors.initials: EJ
authors.lastname: van Zoelen
authors.forename: Koen J
authors.initials: KJ
authors.lastname: Dechering
mesh_terms: D019175:DNA Methylation / Q000187:drug effects*; D004269:DNA, Bacterial / Q000378:metabolism; D015257:DNA-Cytosine Methylases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D057166:High-Throughput Screening Assays / Q000379:methods; D008780:Methyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: D004269:DNA, Bacterial; D004791:Enzyme Inhibitors; C081573:DNA modification methylase SssI; D015257:DNA-Cytosine Methylases; D008780:Methyltransferases