Identification and optimization of hydrazone- gallate derivatives as specific inhibitors of DNA methyltransferase 3A

被引：13

作者：

Erdmann, Alexandre ^{[1
]}

Menon, Yoann ^{[1
]}

Gros, Christina ^{[1
]}

Masson, Veronique ^{[1
]}

Aussagues, Yannick ^{[1
]}

Fleury, Laurence ^{[1
]}

Ausseil, Frederic ^{[1
]}

Novosad, Natacha ^{[1
]}

Schambel, Philippe ^{[2
]}

Baltas, Michel ^{[3
,4
]}

Arimondo, Paola B. ^{[1
]}

机构：

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

[2] Inst Rech Pierre Fabre, F-81106 Castres, France

[3] SPCMIB, Lab Synthese & Physicochim Mol Interet Biol, CNRS, UMR 5068, 118 Route Narbonne, F-31062 Toulouse 9, France

[4] Univ Toulouse, Lab Synthese & Physicochim Mol Interet Biol, UPS, SPCMIB, 118 Route Narbonne, F-31062 Toulouse 9, France

来源：

FUTURE MEDICINAL CHEMISTRY | 2016年 / 8卷 / 04期

关键词：

cancer; chemical modifications; DNA m-ethylation; DNA methyltransferase; epigenetics; gene reactivation; hydrazone-gallate derivatives; inhibitors; molecular docking; structure-activity relationship; METHYLATION; CANCER; EPIGENETICS;

D O I：

10.4155/fmc.15.192

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

DNA methylation is the most studied epigenetic event. Since the methylation profile of the genome is widely modified in cancer cells, DNA methyltransferases are the target of new anticancer therapies. Nucleosidic inhibitors suffer from toxicity and chemical stability, while non-nucleosidic inhibitors lack potency. Here, we found a novel DNMT inhibitor scaffold by enzymatic screening and structure-activity relationship studies. The optimization studies led to an inhibitor containing three fragments: a gallate frame, a hydrazone linker and a benzothiazole moiety. Interestingly, the compound inhibits DNMT3A with micromolar potency (EC50 = 1.6 mu M) and does not inhibit DNMT1; this DNMT(A selectivity is supported by a docking study. Finally, the compound reactivates a reporter gene in leukemia KG-1 cells.

引用

页码：373 / 380

页数：8

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