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

Philos Trans R Soc Lond B Biol Sci. 2018 Jun 5;373(1748):20170150. doi: 10.1098/rstb.2017.0150.

Abstract

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'.

Keywords: apoptosis; autophagy; enhancer of zeste homologue 2 inhibitors; epigenetics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / genetics*
  • Autophagy / genetics*
  • Cell Line, Tumor
  • Enhancer of Zeste Homolog 2 Protein / antagonists & inhibitors*
  • Humans
  • Pyrazoles / pharmacology*

Substances

  • Pyrazoles
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein

Associated data

  • figshare/10.6084/m9.figshare.c.4025029