Pyrazole-based inhibitors of enhancer of zeste homologue 2 induce apoptosis and autophagy in cancer cells

Novel pyrazole-based EZH2 inhibitors have been prepared through a molecular pruning approach from known inhibitors bearing a bicyclic moiety as a central scaffold. The hit compound 1o (N-((4, 6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide) showed low mic...

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Published in:Philosophical transactions of the Royal Society of London. Series B. Biological sciences 2018-06, Vol.373 (1748), p.1-8
Main Authors: Mellini, Paolo, Marrocco, Biagina, Borovika, Diana, Polletta, Lucia, Carnevale, Ilaria, Saladini, Serena, Stazi, Giulia, Zwergel, Clemens, Trapencieris, Peteris, Ferretti, Elisabetta, Tafani, Marco, Valente, Sergio, Mai, Antonello
Format: Article
Language:English
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Summary:Novel pyrazole-based EZH2 inhibitors have been prepared through a molecular pruning approach from known inhibitors bearing a bicyclic moiety as a central scaffold. The hit compound 1o (N-((4, 6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide) showed low micromolar EZH2/PRC2 inhibition and high selectivity towards a panel of other methyltransferases. Moreover, 1o displayed cell growth arrest in breast MDA-MB231, leukaemia K562, and neuroblastoma SK-N-BE cancer cells joined to reduction of H3K27me3 levels and induction of apoptosis and autophagy. This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'.
ISSN:0962-8436
1471-2970