title: C5-DNA methyltransferase inhibitors: from screening to effects on zebrafish embryo development.
abstract: DNA methylation is involved in the regulation of gene expression and plays an important role in normal developmental processes and diseases, such as cancer. DNA methyltransferases are the enzymes responsible for DNA methylation on the position 5 of cytidine in a CpG context. In order to identify and characterize novel inhibitors of these enzymes, we developed a fluorescence-based throughput screening by using a short DNA duplex immobilized on 96-well plates. We have screened 114 flavones and flavanones for the inhibition of the murine catalytic Dnmt3a/3L complex and found 36 hits with IC(50) values in the lower micromolar and high nanomolar ranges. The assay, together with inhibition tests on two other methyltransferases, structure-activity relationships and docking studies, gave insights on the mechanism of inhibition. Finally, two derivatives effected zebrafish embryo development, and induced a global demethylation of the genome, at doses lower than the control drug, 5-azacytidine.
authors.affiliation: UMR 7196 CNRS, MNHN INSERM U565, Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Ceccaldi
authors.forename: Arumugam
authors.initials: A
authors.lastname: Rajavelu
authors.forename: Christine
authors.initials: C
authors.lastname: Champion
authors.forename: Christine
authors.initials: C
authors.lastname: Rampon
authors.forename: Renata
authors.initials: R
authors.lastname: Jurkowska
authors.forename: Gytis
authors.initials: G
authors.lastname: Jankevicius
authors.forename: Catherine
authors.initials: C
authors.lastname: Sénamaud-Beaufort
authors.forename: Loïc
authors.initials: L
authors.lastname: Ponger
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gagey
authors.forename: Hana Dali
authors.initials: HD
authors.lastname: Ali
authors.forename: Jörg
authors.initials: J
authors.lastname: Tost
authors.forename: Sophie
authors.initials: S
authors.lastname: Vriz
authors.forename: Sindu
authors.initials: S
authors.lastname: Ros
authors.forename: Daniel
authors.initials: D
authors.lastname: Dauzonne
authors.forename: Albert
authors.initials: A
authors.lastname: Jeltsch
authors.forename: Dominique
authors.initials: D
authors.lastname: Guianvarc'h
authors.forename: Paola B
authors.initials: PB
authors.lastname: Arimondo
mesh_terms: D000818:Animals; D001483:Base Sequence; D018360:Crystallography, X-Ray; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D047108:Embryonic Development / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D015027:Zebrafish / Q000196:embryology*
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D004248:DNA (Cytosine-5-)-Methyltransferases