title: Properly substituted analogues of BIX-01294 lose inhibition of G9a histone methyltransferase and gain selective anti-DNA methyltransferase 3A activity.
abstract: Chemical manipulations performed on the histone H3 lysine 9 methyltransferases (G9a/GLP) inhibitor BIX-01294 afforded novel desmethoxyquinazolines able to inhibit the DNA methyltransferase DNMT3A at low micromolar levels without any significant inhibition of DNMT1 and G9a. In KG-1 cells such compounds, when tested at sub-toxic doses, induced the luciferase re-expression in a stable construct controlled by a cytomegalovirus (CMV) promoter silenced by methylation (CMV-luc assay). Finally, in human lymphoma U-937 and RAJI cells, the N-(1-benzylpiperidin-4-yl)-2-(4-phenylpiperazin-1-yl)quinazolin-4-amine induced the highest proliferation arrest and cell death induction starting from 10 µM, in agreement with its DNMT3A inhibitory potency.
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Roma, IT.
authors.forename: Dante
authors.initials: D
authors.lastname: Rotili
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Roma, IT.
authors.forename: Domenico
authors.initials: D
authors.lastname: Tarantino
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Roma, IT.
authors.forename: Biagina
authors.initials: B
authors.lastname: Marrocco
authors.affiliation: USR3388 CNRS-Pierre Fabre ETaC, CRDPF, Toulouse, France.
authors.forename: Christina
authors.initials: C
authors.lastname: Gros
authors.affiliation: USR3388 CNRS-Pierre Fabre ETaC, CRDPF, Toulouse, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Masson
authors.affiliation: USR3388 CNRS-Pierre Fabre ETaC, CRDPF, Toulouse, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Poughon
authors.affiliation: USR3388 CNRS-Pierre Fabre ETaC, CRDPF, Toulouse, France.
authors.forename: Fréderic
authors.initials: F
authors.lastname: Ausseil
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Yanqi
authors.initials: Y
authors.lastname: Chang
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Roma, IT.
authors.forename: Donatella
authors.initials: D
authors.lastname: Labella
authors.affiliation: DiSTABiF, Seconda Università di Napoli, Caserta, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Cosconati
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II", Napoli, IT.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Di Maro
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II", Napoli, IT.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: Laboratoire de Biologie Moléculaire et Cellulaire du Cancer (LBMCC), Luxembourg, Luxembourg.
authors.forename: Michael
authors.initials: M
authors.lastname: Schnekenburger
authors.affiliation: Laboratoire de Biologie Moléculaire et Cellulaire du Cancer (LBMCC), Luxembourg, Luxembourg.
authors.forename: Cindy
authors.initials: C
authors.lastname: Grandjenette
authors.affiliation: Laboratoire de Biologie Moléculaire et Cellulaire du Cancer (LBMCC), Luxembourg, Luxembourg.
authors.forename: Celine
authors.initials: C
authors.lastname: Bouvy
authors.affiliation: Laboratoire de Biologie Moléculaire et Cellulaire du Cancer (LBMCC), Luxembourg, Luxembourg; Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Marc
authors.initials: M
authors.lastname: Diederich
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Cheng
authors.affiliation: USR3388 CNRS-Pierre Fabre ETaC, CRDPF, Toulouse, France.
authors.forename: Paola B
authors.initials: PB
authors.lastname: Arimondo
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Roma, IT; Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza Università di Roma, Roma, IT.
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
mesh_terms: D001381:Azepines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000090205:DNA Methyltransferase 3A; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006649:Histocompatibility Antigens / Q000737:chemistry / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D011799:Quinazolines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001381:Azepines; C518299:BIX 01294; C000717967:DNMT3A protein, human; D004791:Enzyme Inhibitors; D006649:Histocompatibility Antigens; D011799:Quinazolines; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase