title: New insights on the mechanism of quinoline-based DNA Methyltransferase inhibitors.
abstract: 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.
authors.affiliation: From the Unité de Service et de Recherche CNRS-Pierre Fabre 3388, ETaC, CRDPF, 31100 Toulouse, France.
authors.forename: Christina
authors.initials: C
authors.lastname: Gros
authors.affiliation: From the Unité de Service et de Recherche CNRS-Pierre Fabre 3388, ETaC, CRDPF, 31100 Toulouse, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Fleury
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale (IPBS) CNRS, Toulouse, 31077, France, Université de Toulouse, UPS, IPBS, Toulouse, 31077, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Nahoum
authors.affiliation: From the Unité de Service et de Recherche CNRS-Pierre Fabre 3388, ETaC, CRDPF, 31100 Toulouse, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Faux
authors.affiliation: Sapienza University of Rome, Department of Chemistry and Technology of Drug, Sapienza University of Rome, I-00185 Roma, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Valente
authors.affiliation: Sapienza University of Rome, Department of Chemistry and Technology of Drug, Sapienza University of Rome, I-00185 Roma, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Labella
authors.affiliation: From the Unité de Service et de Recherche CNRS-Pierre Fabre 3388, ETaC, CRDPF, 31100 Toulouse, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Cantagrel
authors.affiliation: From the Unité de Service et de Recherche CNRS-Pierre Fabre 3388, ETaC, CRDPF, 31100 Toulouse, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Rilova
authors.affiliation: INSERM UMR837-JPARC (Jean-Pierre Aubert Research Center), Team 4, IRCL, 59045 Lille, France.
authors.forename: Mohamed Amine
authors.initials: MA
authors.lastname: Bouhlel
authors.affiliation: INSERM UMR837-JPARC (Jean-Pierre Aubert Research Center), Team 4, IRCL, 59045 Lille, France.
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: David-Cordonnier
authors.affiliation: From the Unité de Service et de Recherche CNRS-Pierre Fabre 3388, ETaC, CRDPF, 31100 Toulouse, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dufau
authors.affiliation: From the Unité de Service et de Recherche CNRS-Pierre Fabre 3388, ETaC, CRDPF, 31100 Toulouse, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Ausseil
authors.affiliation: Sapienza University of Rome, Department of Chemistry and Technology of Drug, Sapienza University of Rome, I-00185 Roma, Italy, Pasteur Institute-Cenci Bolognetti Foundation, Sapienza University of Rome, I-00185 Roma, Italy, and.
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale (IPBS) CNRS, Toulouse, 31077, France, Université de Toulouse, UPS, IPBS, Toulouse, 31077, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Mourey
authors.affiliation: CNRS UMR 5099, LBME, 31062 Toulouse, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Lacroix
authors.affiliation: From the Unité de Service et de Recherche CNRS-Pierre Fabre 3388, ETaC, CRDPF, 31100 Toulouse, France, paola.arimondo@etac.cnrs.fr.
authors.forename: Paola B
authors.initials: PB
authors.lastname: Arimondo
mesh_terms: D000634:Aminoquinolines / Q000737:chemistry* / Q000494:pharmacology; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D057890:Epigenomics; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000634:Aminoquinolines; D004791:Enzyme Inhibitors; D011743:Pyrimidines; C581203:SGI-1027; D004247:DNA; D004248:DNA (Cytosine-5-)-Methyltransferases; C001920:4-aminoquinoline
keywords: Competition; DNA; DNA Methyltransferase; DNA-Protein Interaction; Enzyme Inhibitor; Gene Regulation; Inhibition Mechanism; SGI-1027