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

Authors
  • Rotili, Dante
  • Tarantino, Domenico
  • Marrocco, Biagina
  • Gros, Christina
  • Masson, Véronique
  • Poughon, Valérie
  • Ausseil, Fréderic
  • Chang, Yanqi
  • Labella, Donatella
  • Cosconati, Sandro
  • Di Maro, Salvatore
  • Novellino, Ettore
  • Michael Schnekenburger
  • Cindy Grandjenette
  • Bouvy, Celine
  • Marc Diederich
  • Cheng, Xiaodong
  • Arimondo, Paola B.
  • Mai, Antonello
Type
Published Article
Journal
PLoS ONE
Publisher
Public Library of Science
Publication Date
May 07, 2014
Volume
9
Issue
5
Identifiers
DOI: 10.1371/journal.pone.0096941
Source
LBMCC
Keywords
License
Green

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.

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