期刊
CHEMBIOCHEM
卷 12, 期 9, 页码 1337-1345出版社
WILEY-BLACKWELL
DOI: 10.1002/cbic.201100130
关键词
DNA methylation; DNMT; flavones; high-throughput screening; inhibitors
资金
- ANR [JCJC06 JCJC06 0080-01]
- DFG [JE 252/6]
- ARC
- INSERM-CNRS BDI
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据