Properly Substituted Analogues of BIX-01294 Lose Inhibition of G9a Histone Methyltransferase and Gain Selective Anti-DNA Methyltransferase 3A Activity
| Autor: | 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 |
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| Přispěvatelé: | 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, Antonello, Mai |
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
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 |
| Zdroj: | PLoS ONE PLoS ONE, Public Library of Science, 2014, 9 (5), pp.e96941. ⟨10.1371/journal.pone.0096941⟩ PLoS ONE, 2014, 9 (5), pp.e96941. ⟨10.1371/journal.pone.0096941⟩ PLoS ONE, Vol 9, Iss 5, p e96941 (2014) |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0096941⟩ |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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