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

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

doi:10.1371/journal.pone.0096941

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

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

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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.

Original language	English
Article number	e96941
Journal	PLoS ONE
Volume	9
Issue number	5
DOIs	https://doi.org/10.1371/journal.pone.0096941
Publication status	Published - 8 May 2014
Externally published	Yes

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Rotili, D., Tarantino, D., Marrocco, B., Gros, C., Masson, V., Poughon, V., Ausseil, F., Chang, Y., Labella, D., Cosconati, S., Di Maro, S., Novellino, E., Schnekenburger, M., Grandjenette, C., Bouvy, C., Diederich, M., Cheng, X., Arimondo, P. B., & Mai, A. (2014). Properly substituted analogues of BIX-01294 lose inhibition of G9a histone methyltransferase and gain selective anti-DNA methyltransferase 3A activity. PLoS ONE, 9(5), Article e96941. https://doi.org/10.1371/journal.pone.0096941

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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.",

author = "Dante Rotili and Domenico Tarantino and Biagina Marrocco and Christina Gros and V{\'e}ronique Masson and Val{\'e}rie Poughon and Fr{\'e}deric Ausseil and Yanqi Chang and Donatella Labella and Sandro Cosconati and \{Di Maro\}, Salvatore and Ettore Novellino and Michael Schnekenburger and Cindy Grandjenette and Celine Bouvy and Marc Diederich and Xiaodong Cheng and Arimondo, \{Paola B.\} and Antonello Mai",

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doi = "10.1371/journal.pone.0096941",

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Rotili, D, Tarantino, D, Marrocco, B, Gros, C, Masson, V, Poughon, V, Ausseil, F, Chang, Y, Labella, D, Cosconati, S, Di Maro, S, Novellino, E, Schnekenburger, M, Grandjenette, C, Bouvy, C, Diederich, M, Cheng, X, Arimondo, PB & Mai, A 2014, 'Properly substituted analogues of BIX-01294 lose inhibition of G9a histone methyltransferase and gain selective anti-DNA methyltransferase 3A activity', PLoS ONE, vol. 9, no. 5, e96941. https://doi.org/10.1371/journal.pone.0096941

TY - JOUR

T1 - Properly substituted analogues of BIX-01294 lose inhibition of G9a histone methyltransferase and gain selective anti-DNA methyltransferase 3A activity

AU - Rotili, Dante

AU - Tarantino, Domenico

AU - Marrocco, Biagina

AU - Gros, Christina

AU - Masson, Véronique

AU - Poughon, Valérie

AU - Ausseil, Fréderic

AU - Chang, Yanqi

AU - Labella, Donatella

AU - Cosconati, Sandro

AU - Di Maro, Salvatore

AU - Novellino, Ettore

AU - Schnekenburger, Michael

AU - Grandjenette, Cindy

AU - Bouvy, Celine

AU - Diederich, Marc

AU - Cheng, Xiaodong

AU - Arimondo, Paola B.

AU - Mai, Antonello

PY - 2014/5/8

Y1 - 2014/5/8

N2 - 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.

AB - 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.

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DO - 10.1371/journal.pone.0096941

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JF - PLoS ONE

IS - 5

M1 - e96941

ER -

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

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