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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.
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https://hal.archives-ouvertes.fr/hal-00632453
Contributor : Nicolas Perron <>
Submitted on : Friday, October 14, 2011 - 1:42:26 PM
Last modification on : Tuesday, December 15, 2020 - 4:02:05 AM

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Alexandre Ceccaldi, Arumugam Rajavelu, Christine Champion, Christine Rampon, Renata Jurkowska, et al.. C5-DNA methyltransferase inhibitors: from screening to effects on zebrafish embryo development.. ChemBioChem, Wiley-VCH Verlag, 2011, (12) (9), pp.1337-45. ⟨10.1002/cbic.201100130⟩. ⟨hal-00632453⟩

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