New Insights on the Mechanism of Quinoline-based DNA Methyltransferase Inhibitors

作者：Christina Gros, Laurence Fleury, Virginie Nahoum, Céline Faux, Sérgio Valente, Donatella Labella, Frédéric Cantagrel, Elodie Rilova, Mohamed Amine Bouhlel, Marie‐Hélène David‐Cordonnier, Isabelle Dufau, Fréderic Ausseil, Antonello Mai, Lionel Mourey, Laurent Lacroix, Paola B. Arimondo · 发表于：Journal of Biological Chemistry · 年份：2014 · DOI：10.1074/jbc.m114.594671 · 被引用次数：71 · 研究领域：Epigenetics and DNA Methylation、RNA modifications and cancer、DNA Repair Mechanisms

Among the epigenetic marks, DNA methylation is one of the most studied. It is highly deregulated in numerous diseases, including cancer. Indeed, it has been shown that hypermethylation of tumor suppressor genes promoters is a common feature of cancer cells. Because DNA methylation is reversible, the DNA methyltransferases (DNMTs), responsible for this epigenetic mark, are considered promising therapeutic targets. Several molecules have been identified as DNMT inhibitors and, among the non-nucleoside inhibitors, 4-aminoquinoline-based inhibitors, such as SGI-1027 and its analogs, showed potent inhibitory activity. Here we characterized the in vitro mechanism of action of SGI-1027 and two analogs. Enzymatic competition studies with the DNA substrate and the methyl donor cofactor, S-adenosyl-l-methionine (AdoMet), displayed AdoMet non-competitive and DNA competitive behavior. In addition, deviations from the Michaelis-Menten model in DNA competition experiments suggested an interaction with DNA. Thus their ability to interact with DNA was established; although SGI-1027 was a weak DNA ligand, analog 5, the most potent inhibitor, strongly interacted with DNA. Finally, as 5 interacted with DNMT only when the DNA duplex was present, we hypothesize that this class of chemical compounds inhibit DNMTs by interacting with the DNA substrate.