Identification of Novel Inhibitors of DNA Methylation by Screening of a Chemical Library

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• 作者：Alexandre Ceccaldi ; Arumugam Rajavelu ; Sergey Ragozin ; Catherine S茅namaud-Beaufort ; Pavel Bashtrykov ; No茅 Testa ; Hana Dali-Ali ; Christine Maulay-Bailly ; S茅verine Amand ; Dominique Guianvarc鈥檋 ; Albert Jeltsch ; Paola B. Arimondo
• 刊名：ACS Chemical Biology
• 出版年：2013
• 出版时间：March 15, 2013
• 年：2013
• 卷：8
• 期：3
• 页码：543-548
• 全文大小：312K
• 年卷期：v.8,no.3(March 15, 2013)
• ISSN：1554-8937

文摘

In order to discover new inhibitors of the DNA methyltransferase 3A/3L complex, we used a medium-throughput nonradioactive screen on a random collection of 1120 small organic compounds. After a primary hit detection against DNA methylation activity of the murine Dnmt3A/3L catalytic complex, we further evaluated the EC₅₀ of the 12 most potent hits as well as their cytotoxicity on DU145 prostate cancer cultured cells. Interestingly, most of the inhibitors showed low micromolar activities and little cytotoxicity. Dichlone, a small halogenated naphthoquinone, classically used as pesticide and fungicide, showed the lowest EC₅₀ at 460 nM. We briefly assessed the selectivity of a subset of our new inhibitors against hDNMT1 and bacterial Dnmts, including M. SssI and EcoDam, and the protein lysine methyltransferase PKMT G9a and the mode of inhibition. Globally, the tested molecules showed a clear preference for the DNA methyltransferases, but poor selectivity among them. Two molecules including Dichlone efficiently reactivated YFP gene expression in a stable HEK293 cell line by promoter demethylation. Their efficacy was comparable to the DNMT inhibitor of reference 5-azacytidine.