1. Properly Substituted Analogues of BIX-01294 Lose Inhibition of G9a Histone Methyltransferase and Gain Selective Anti-DNA Methyltransferase 3A Activity
- Author
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Manfred Jung, Dante Rotili, Domenico Tarantino, Biagina Marrocco, Christina Gros, Veronique Masson, Valerie Poughon, Frederic Ausseil, Yanqi Chang, Donatella Labella, Sandro Cosconati, Salvatore Di Maro, Michael Schnekenburger, Cindy Grandjenette, Celine Bouvy, Marc Diederich, Xiaodong Cheng, Paola B. Arimondo, Antonello Mai, NOVELLINO, ETTORE, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Pharmacochimie de la Régulation Epigénétique du Cancer (ETaC), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-PIERRE FABRE, Emory University School of Medicine, Emory University [Atlanta, GA], Seconda Università degli studi di Napoli, Università degli studi di Napoli Federico II, Laboratoire de Biologie Moléculaire et Cellulaire du Cancer [Luxembourg] (LBMCC), Hôpital Kirchberg [Luxembourg], Seoul National University [Seoul] (SNU), Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP), This work was supported by PRIN 2009PX2T2E, FIRB RBFR10ZJQT, Progetto Ateneo Sapienza 2012, Progetto IIT-Sapienza, FP7 Projects BLUEPRINT/282510 and COST/TD0905, the U.S. National Institutes of Health (5R01GM049245-20 and 1DP3DK094346-01), the FNRS Télévie Luxembourg grant 7.4612.12.F, the «Recherche Cancer et Sang foundation, and the «Recherches Scientifiques Luxembourg and «Een Häerz fir Kriibskrank Kanner associations. X. Cheng is a Georgia Research Alliance Eminent Scholar. P.B. Arimondo is supported by ATIP CNRS and Région Midi-Pyrenées (Equipe d’Excellence and FEDER). M. Schnekenburger is supported by a 'Waxweiler grant for cancer prevention research' from the Action Lions 'Vaincre le Cancer'. C. Gros is supported by Fondation de la Recherche Médicale. C. Grandjenette is a recipient of a postdoctoral grant from FNRS Télévie Luxembourg. M. Diederich is supported by the NRF by the MEST of Korea for Tumor Microenvironment GCRC 2012-0001184 grant., European Project: 282510,EC:FP7:HEALTH,FP7-HEALTH-2011-single-stage,BLUEPRINT(2011), Rotili, D, Tarantino, D, Marrocco, B, Gros, C, Masson, V, Poughon, V, Ausseil, F, Chang, Y, Labella, D, Cosconati, Sandro, DI MARO, Salvatore, Novellino, E, Schnekenburger, M, Grandjenette, C, Bouvy, C, Diederich, M, Cheng, X, Arimondo, Pb, Mai, A., Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), PIERRE FABRE-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Seconda Università degli Studi di Napoli = Second University of Naples, University of Naples Federico II = Università degli studi di Napoli Federico II, Manfred, Jung, Dante, Rotili, Domenico, Tarantino, Biagina, Marrocco, Christina, Gro, Veronique, Masson, Valerie, Poughon, Frederic, Ausseil, Yanqi, Chang, Donatella, Labella, Sandro, Cosconati, Salvatore Di, Maro, Novellino, Ettore, Michael, Schnekenburger, Cindy, Grandjenette, Celine, Bouvy, Marc, Diederich, Xiaodong, Cheng, Paola B., Arimondo, and Antonello, Mai
- Subjects
Methyltransferase ,Cancer Treatment ,lcsh:Medicine ,MESH: Catalytic Domain ,Biochemistry ,DNA Methyltransferase 3A ,MESH: Structure-Activity Relationship ,Catalytic Domain ,Histocompatibility Antigens ,Molecular Cell Biology ,Medicine and Health Sciences ,DNA (Cytosine-5-)-Methyltransferases ,Enzyme Inhibitors ,lcsh:Science ,Multidisciplinary ,biology ,Cell Death ,Chemical Synthesis ,Histone Modification ,Heterocycle Structures ,Methylation ,Azepines ,3. Good health ,Molecular Docking Simulation ,Chemistry ,MESH: Quinazolines ,Histone ,Oncology ,MESH: Cell Survival ,Cell Processes ,MESH: Enzyme Inhibitors ,Histone methyltransferase ,DNA methylation ,Physical Sciences ,Epigenetics ,DNA modification ,Research Article ,MESH: DNA (Cytosine-5-)-Methyltransferases ,MESH: Cell Line, Tumor ,Cell Survival ,Research and Analysis Methods ,DNA methyltransferase ,Cell Growth ,Epigenetic Therapy ,Histone H3 ,Structure-Activity Relationship ,Cell Line, Tumor ,MESH: Cell Proliferation ,Genetics ,MESH: Molecular Docking Simulation ,Humans ,[CHIM]Chemical Sciences ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Cell Proliferation ,MESH: Humans ,Biology and life sciences ,lcsh:R ,Organic Chemistry ,MESH: Histocompatibility Antigens ,MESH: Histone-Lysine N-Methyltransferase ,Histone-Lysine N-Methyltransferase ,DNA ,Cell Biology ,Molecular biology ,biology.protein ,DNMT1 ,Quinazolines ,lcsh:Q ,Medicinal Chemistry ,MESH: Azepines - Abstract
International audience; 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.
- Published
- 2014
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