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C5-DNA methyltransferase inhibitors: from screening to effects on zebrafish embryo development

Ceccaldi, Alexandre, Rajavelu, Arumugam, Champion, Christine, Rampon, Christine, Jurkowska, Renata ORCID:, Jankevicius, Gytis, Sénamaud-Beaufort, Catherine, Ponger, Loïc, Gagey, Nathalie, Dali Ali, Hana, Tost, Jörg, Vriz, Sophie, Ros, Sindu, Dauzonne, Daniel, Jeltsch, Albert, Guianvarc'h, Dominique and Arimondo, Paola B. 2011. C5-DNA methyltransferase inhibitors: from screening to effects on zebrafish embryo development. ChemBioChem 12 (9) , pp. 1337-1345. 10.1002/cbic.201100130

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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 IC50 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: Wiley
ISSN: 1439-4227
Last Modified: 09 Nov 2022 10:22

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