Design and synthesis of new non nucleoside inhibitors of DNMT3A

被引：19

作者：

Erdmann, Alexandre ^{[1
]}

Menon, Yoann ^{[1
]}

Gros, Christina ^{[1
]}

Molinier, Nicolas ^{[1
]}

Novosad, Natacha ^{[1
]}

Samson, Arnaud ^{[1
]}

Gregoire, Jean-Marc ^{[1
]}

Long, Christophe ^{[1
]}

Ausseil, Frederic ^{[1
]}

Halby, Ludovic ^{[1
]}

Arimondo, Paola B. ^{[1
]}

机构：

[1] CRDPF, ETaC, Unite Serv & Rech CNRS Pierre Fabre 3388, F-31100 Toulouse, France

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2015年 / 23卷 / 17期

关键词：

DNA methylation; DNMT3A; Reactive inhibitor; Michael acceptor; TUMOR-SUPPRESSOR GENES; DNA METHYLATION;

D O I：

10.1016/j.bmc.2015.06.066

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

DNA methylation, an epigenetic modification regulating gene expression, is a promising target in cancer. In an effort to identify new non nucleosidic inhibitors of DNA methyltransferases, the enzymes responsible for DNA methylation, we carried out a high-throughput screening of 66,000 chemical compounds based on an enzymatic assay against catalytic DNMT3A. A family of propiophenone derivatives was identified. After chemical optimization and structure activity relationship studies, a new inhibitor ( 33) was obtained with an EC50 of 2.1 mu M against DNMT3A. The mechanism of inhibition of the compound was investigated as it forms a reactive Michael acceptor group in situ. Thereby, the Michael acceptor 20 was identified. This compound was further characterized for its biological activity in cancer cells. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：5946 / 5953

页数：8

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