Properly Substituted Analogues of BIX-01294 Lose Inhibition of G9a Histone Methyltransferase and Gain Selective Anti-DNA Methyltransferase 3A Activity

Dante Rotili (1) , Domenico Tarantino (1) , Biagina Marrocco (1) , Christina Gros (2) , Véronique Masson (2) , Valérie Poughon (2) , Frédéric Ausseil (2) , Yanqi Chang (3) , Donatella Labella (1) , Sandro Cosconati (4) , Salvatore Di Maro (5) , Ettore Novellino (5) , Michael Schnekenburger (6) , Cindy Grandjenette (6) , Celine Bouvy (6) , Marc Diederich (6, 7) , Xiaodong Cheng (3) , Paola B Arimondo (2) , Antonello Mai (1, 8)

1 UNIROMA - Università degli Studi di Roma "La Sapienza" = Sapienza University [Rome]
2 ETaC - Pharmacochimie de la Régulation Epigénétique du Cancer
3 Emory University School of Medicine
4 Seconda Università degli Studi di Napoli = Second University of Naples
5 University of Naples Federico II = Università degli studi di Napoli Federico II
6 LBMCC - Laboratoire de Biologie Moléculaire et Cellulaire du Cancer [Luxembourg]
7 SNU - Seoul National University [Seoul]
8 Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti

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.

Domaines: Chimie; Biochimie, Biologie Moléculaire

Dante Rotili, Domenico Tarantino, Biagina Marrocco, Christina Gros, Véronique Masson, et al.. Properly Substituted Analogues of BIX-01294 Lose Inhibition of G9a Histone Methyltransferase and Gain Selective Anti-DNA Methyltransferase 3A Activity. PLoS ONE, 2014, 9 (5), pp.e96941. ⟨10.1371/journal.pone.0096941⟩. ⟨pasteur-03182293⟩