5-Methoxyquinoline Derivatives as a New Class of EZH2 Inhibitors

Molecules. 2015 Apr 27;20(5):7620-36. doi: 10.3390/molecules20057620.

Abstract

A series of quinoline derivatives was synthesized and biologically evaluated as Enhancer of Zeste Homologue 2 (EZH2) inhibitors. Structure-activity relationship (SAR) studies led to the discovery of 5-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinolin-4-amine (5k), which displayed an IC50 value of 1.2 μM against EZH2, decreased global H3K27me3 level in cells and also showed good anti-viability activities against two tumor cell lines. Due to the low molecular weight and the fact that no quinoline derivative has been reported as an EZH2 inhibitor, this compound could serve as a lead compound for further optimization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoquinolines / chemical synthesis
  • Aminoquinolines / pharmacology*
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Azepines / chemical synthesis
  • Azepines / pharmacology*
  • Cell Line, Tumor
  • DNA Methylation / genetics
  • Enhancer of Zeste Homolog 2 Protein
  • Histones / genetics
  • Humans
  • Neoplasms / pathology
  • Polycomb Repressive Complex 2 / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • 5-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinolin-4-amine
  • Aminoquinolines
  • Antineoplastic Agents
  • Azepines
  • Histones
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2