title: Design and synthesis of new non nucleoside inhibitors of DNMT3A.
abstract: DNA methylation, an epigenetic modification regulating gene expression, is a promising target in cancer. In an effort to identify new non nucleosidic inhibitors of DNA methyltransferases, the enzymes responsible for DNA methylation, we carried out a high-throughput screening of 66,000 chemical compounds based on an enzymatic assay against catalytic DNMT3A. A family of propiophenone derivatives was identified. After chemical optimization and structure activity relationship studies, a new inhibitor (33) was obtained with an EC50 of 2.1 μM against DNMT3A. The mechanism of inhibition of the compound was investigated as it forms a reactive Michael acceptor group in situ. Thereby, the Michael acceptor 20 was identified. This compound was further characterized for its biological activity in cancer cells.
authors.affiliation: Unité de Service et de Recherche CNRS-Pierre Fabre n°3388, ETaC, CRDPF, 3 Avenue Hubert Curien, 31100 Toulouse, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Erdmann
authors.affiliation: Unité de Service et de Recherche CNRS-Pierre Fabre n°3388, ETaC, CRDPF, 3 Avenue Hubert Curien, 31100 Toulouse, France.
authors.forename: Yoann
authors.initials: Y
authors.lastname: Menon
authors.affiliation: Unité de Service et de Recherche CNRS-Pierre Fabre n°3388, ETaC, CRDPF, 3 Avenue Hubert Curien, 31100 Toulouse, France.
authors.forename: Christina
authors.initials: C
authors.lastname: Gros
authors.affiliation: Unité de Service et de Recherche CNRS-Pierre Fabre n°3388, ETaC, CRDPF, 3 Avenue Hubert Curien, 31100 Toulouse, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Molinier
authors.affiliation: Unité de Service et de Recherche CNRS-Pierre Fabre n°3388, ETaC, CRDPF, 3 Avenue Hubert Curien, 31100 Toulouse, France.
authors.forename: Natacha
authors.initials: N
authors.lastname: Novosad
authors.affiliation: Unité de Service et de Recherche CNRS-Pierre Fabre n°3388, ETaC, CRDPF, 3 Avenue Hubert Curien, 31100 Toulouse, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Samson
authors.affiliation: Unité de Service et de Recherche CNRS-Pierre Fabre n°3388, ETaC, CRDPF, 3 Avenue Hubert Curien, 31100 Toulouse, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Gregoire
authors.affiliation: Unité de Service et de Recherche CNRS-Pierre Fabre n°3388, ETaC, CRDPF, 3 Avenue Hubert Curien, 31100 Toulouse, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Long
authors.affiliation: Unité de Service et de Recherche CNRS-Pierre Fabre n°3388, ETaC, CRDPF, 3 Avenue Hubert Curien, 31100 Toulouse, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Ausseil
authors.affiliation: Unité de Service et de Recherche CNRS-Pierre Fabre n°3388, ETaC, CRDPF, 3 Avenue Hubert Curien, 31100 Toulouse, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Halby
authors.affiliation: Unité de Service et de Recherche CNRS-Pierre Fabre n°3388, ETaC, CRDPF, 3 Avenue Hubert Curien, 31100 Toulouse, France. Electronic address: paola.arimondo@etac.cnrs.fr.
authors.forename: Paola B
authors.initials: PB
authors.lastname: Arimondo
mesh_terms: D004248:DNA (Cytosine-5-)-Methyltransferases / Q000138:chemical synthesis* / Q000737:chemistry*; D000090205:DNA Methyltransferase 3A; D057890:Epigenomics; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: C000717967:DNMT3A protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A
keywords: DNA methylation; DNMT3A; Michael acceptor; Reactive inhibitor