Design, synthesis and activity evaluation of quinolinone derivatives as EZH2 inhibitors

Bioorg Med Chem Lett. 2024 Jun 1:105:129726. doi: 10.1016/j.bmcl.2024.129726. Epub 2024 Apr 3.

Abstract

The enhancer of zeste homologue 2 (EZH2) is the core catalytic subunit of polycomb repressive complex 2, which catalyzes lysine 27 methylation of histone H3. Herein, a series of quinolinone derivatives were designed and synthesized based on the structure of Tazemetostat as the lead compound. Compound 9l (EZH2WT IC50 = 0.94 nM) showed stronger antiproliferative activity in HeLa cells than the lead compound. Moreover, compound 9e (EZH2WT IC50 = 1.01 nM) significantly inhibited the proliferation and induced apoptosis in A549 cells.

Keywords: Anti-tumor; EZH2 inhibitor; PRC2; Quinolinone derivatives.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation* / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Enhancer of Zeste Homolog 2 Protein* / antagonists & inhibitors
  • Enhancer of Zeste Homolog 2 Protein* / metabolism
  • HeLa Cells
  • Humans
  • Molecular Structure
  • Quinolones* / chemical synthesis
  • Quinolones* / chemistry
  • Quinolones* / pharmacology
  • Structure-Activity Relationship

Substances

  • Quinolones
  • Enhancer of Zeste Homolog 2 Protein
  • EZH2 protein, human
  • Antineoplastic Agents