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

Research output: Contribution to journalArticle

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 languageEnglish
Pages (from-to)e96941
JournalPLoS ONE
Volume9
Issue number5
DOIs
Publication statusPublished - 2014

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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), e96941. https://doi.org/10.1371/journal.pone.0096941