title: Identification and optimization of hydrazone-gallate derivatives as specific inhibitors of DNA methyltransferase 3A.
abstract: 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 μM) and does not inhibit DNMT1; this DNMT3A selectivity is supported by a docking study. Finally, the compound reactivates a reporter gene in leukemia KG-1 cells.
authors.affiliation: Unité de Service et de Recherche CNRS-Pierre Fabre USR n°3388, ETaC, CRDPF, 31100 Toulouse, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Erdmann
authors.affiliation: Unité de Service et de Recherche CNRS-Pierre Fabre USR n°3388, ETaC, CRDPF, 31100 Toulouse, France.
authors.forename: Yoann
authors.initials: Y
authors.lastname: Menon
authors.affiliation: Unité de Service et de Recherche CNRS-Pierre Fabre USR n°3388, ETaC, CRDPF, 31100 Toulouse, France.
authors.forename: Christina
authors.initials: C
authors.lastname: Gros
authors.affiliation: Unité de Service et de Recherche CNRS-Pierre Fabre USR n°3388, ETaC, CRDPF, 31100 Toulouse, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Masson
authors.affiliation: Unité de Service et de Recherche CNRS-Pierre Fabre USR n°3388, ETaC, CRDPF, 31100 Toulouse, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Aussagues
authors.affiliation: Unité de Service et de Recherche CNRS-Pierre Fabre USR n°3388, ETaC, CRDPF, 31100 Toulouse, France.
authors.forename: Fréderic
authors.initials: F
authors.lastname: Ausseil
authors.affiliation: Unité de Service et de Recherche CNRS-Pierre Fabre USR n°3388, ETaC, CRDPF, 31100 Toulouse, France.
authors.forename: Natacha
authors.initials: N
authors.lastname: Novosad
authors.affiliation: Institut de Recherche Pierre Fabre, 81106 Castres, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Schambel
authors.affiliation: CNRS, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, SPCMIB, UMR-5068, 118 Route de Narbonne, 31062 Toulouse cedex 9, France.|Université de Toulouse, UPS, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, SPCMIB, 118 route de Narbonne,31062 Toulouse cedex 9, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Baltas
authors.affiliation: Unité de Service et de Recherche CNRS-Pierre Fabre USR n°3388, ETaC, CRDPF, 31100 Toulouse, France.
authors.forename: Paola B
authors.initials: PB
authors.lastname: Arimondo
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000090205:DNA Methyltransferase 3A; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005707:Gallic Acid / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; C000717967:DNMT3A protein, human; D004791:Enzyme Inhibitors; D006835:Hydrazones; D005707:Gallic Acid; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A
keywords: DNA methylation; DNA methyltransferase; cancer; chemical modifications; epigenetics; gene reactivation; hydrazone-gallate derivatives; inhibitors; molecular docking; structure–activity relationship