Properly substituted analogues of BIX-01294 lose inhibition of G9a histone methyltransferase and gain selective anti-DNA methyltransferase 3A activity.

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 compoun...

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Main Authors:	Dante Rotili, Domenico Tarantino, Biagina Marrocco, Christina Gros, Véronique Masson, Valérie Poughon, Fréderic Ausseil, Yanqi Chang, Donatella Labella, Sandro Cosconati, Salvatore Di Maro, Ettore Novellino, Michael Schnekenburger, Cindy Grandjenette, Celine Bouvy, Marc Diederich, Xiaodong Cheng, Paola B Arimondo, Antonello Mai
Format:	Article
Language:	English
Published:	Public Library of Science (PLoS) 2014-01-01
Series:	PLoS ONE
Online Access:	http://europepmc.org/articles/PMC4014597?pdf=render

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spelling	doaj-281a01d650e04497b3316ad698b79eb42020-11-25T01:58:54ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0195e9694110.1371/journal.pone.0096941Properly substituted analogues of BIX-01294 lose inhibition of G9a histone methyltransferase and gain selective anti-DNA methyltransferase 3A activity.Dante RotiliDomenico TarantinoBiagina MarroccoChristina GrosVéronique MassonValérie PoughonFréderic AusseilYanqi ChangDonatella LabellaSandro CosconatiSalvatore Di MaroEttore NovellinoMichael SchnekenburgerCindy GrandjenetteCeline BouvyMarc DiederichXiaodong ChengPaola B ArimondoAntonello MaiChemical 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.http://europepmc.org/articles/PMC4014597?pdf=render
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Dante Rotili Domenico Tarantino Biagina Marrocco Christina Gros Véronique Masson Valérie Poughon Fréderic Ausseil Yanqi Chang Donatella Labella Sandro Cosconati Salvatore Di Maro Ettore Novellino Michael Schnekenburger Cindy Grandjenette Celine Bouvy Marc Diederich Xiaodong Cheng Paola B Arimondo Antonello Mai
spellingShingle	Dante Rotili Domenico Tarantino Biagina Marrocco Christina Gros Véronique Masson Valérie Poughon Fréderic Ausseil Yanqi Chang Donatella Labella Sandro Cosconati Salvatore Di Maro Ettore Novellino Michael Schnekenburger Cindy Grandjenette Celine Bouvy Marc Diederich Xiaodong Cheng Paola B Arimondo Antonello Mai Properly substituted analogues of BIX-01294 lose inhibition of G9a histone methyltransferase and gain selective anti-DNA methyltransferase 3A activity. PLoS ONE
author_facet	Dante Rotili Domenico Tarantino Biagina Marrocco Christina Gros Véronique Masson Valérie Poughon Fréderic Ausseil Yanqi Chang Donatella Labella Sandro Cosconati Salvatore Di Maro Ettore Novellino Michael Schnekenburger Cindy Grandjenette Celine Bouvy Marc Diederich Xiaodong Cheng Paola B Arimondo Antonello Mai
author_sort	Dante Rotili
title	Properly substituted analogues of BIX-01294 lose inhibition of G9a histone methyltransferase and gain selective anti-DNA methyltransferase 3A activity.
title_short	Properly substituted analogues of BIX-01294 lose inhibition of G9a histone methyltransferase and gain selective anti-DNA methyltransferase 3A activity.
title_full	Properly substituted analogues of BIX-01294 lose inhibition of G9a histone methyltransferase and gain selective anti-DNA methyltransferase 3A activity.
title_fullStr	Properly substituted analogues of BIX-01294 lose inhibition of G9a histone methyltransferase and gain selective anti-DNA methyltransferase 3A activity.
title_full_unstemmed	Properly substituted analogues of BIX-01294 lose inhibition of G9a histone methyltransferase and gain selective anti-DNA methyltransferase 3A activity.
title_sort	properly substituted analogues of bix-01294 lose inhibition of g9a histone methyltransferase and gain selective anti-dna methyltransferase 3a activity.
publisher	Public Library of Science (PLoS)
series	PLoS ONE
issn	1932-6203
publishDate	2014-01-01
description	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.
url	http://europepmc.org/articles/PMC4014597?pdf=render
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Properly substituted analogues of BIX-01294 lose inhibition of G9a histone methyltransferase and gain selective anti-DNA methyltransferase 3A activity.

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