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C5‐DNA Methyltransferase Inhibitors: From Screening to Effects on Zebrafish Embryo Development
Author(s) -
Ceccaldi Alexandre,
Rajavelu Arumugam,
Champion Christine,
Rampon Christine,
Jurkowska Renata,
Jankevicius Gytis,
SénamaudBeaufort Catherine,
Ponger Loïc,
Gagey Nathalie,
Dali Ali Hana,
Tost Jörg,
Vriz Sophie,
Ros Sindu,
Dauzonne Daniel,
Jeltsch Albert,
Guianvarc'h Dominique,
Arimondo Paola B.
Publication year - 2011
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201100130
Subject(s) - methyltransferase , dna methylation , zebrafish , dna , dna demethylation , biology , dna methyltransferase , biochemistry , dnmt1 , flavones , enzyme , cpg site , methylation , cytidine , chemistry , gene , gene expression , genetics
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.