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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Detalles Bibliográficos
Autores principales: 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, Schnekenburger, Michael, Grandjenette, Cindy, Bouvy, Celine, Diederich, Marc, Cheng, Xiaodong, Arimondo, Paola B., Mai, Antonello
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Research Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014597/
https://www.ncbi.nlm.nih.gov/pubmed/24810902
http://dx.doi.org/10.1371/journal.pone.0096941
Descripción
Sumario: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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