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 inPhilosophical transactions of the Royal Society of London. Series B. Biological sciences Vol. 373; no. 1748; pp. 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 Journal Article
LanguageEnglish
Published Royal Society 05.06.2018
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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