Design and synthesis of (E)-1,2-diphenylethene-based EZH2 inhibitors

Bioorg Med Chem Lett. 2020 Mar 1;30(5):126957. doi: 10.1016/j.bmcl.2020.126957. Epub 2020 Jan 7.

Abstract

Enhancer of zeste homolog 2 (EZH2) serves as the catalytic subunit of the polycomb repression complex 2 (PRC2), which is implicated in cancer progression metastasis and poor prognosis. Based on our EZH2 inhibitor SKLB1049 with low nanomolar activity, we extended the "tail" region to get a series of (E)-1,2-diphenylethene derivatives as novel EZH2 inhibitors. SAR exploration and preliminary assessment led to the discovery of the potent novel EZH2 inhibitor 9b (EZH2WT IC50 = 22.0 nM). Compound 9b inhibited the proliferation of WSU-DLCL2 and SU-DHL-4 cell lines (IC50 = 1.61 µM and 2.34 µM, respectively). The biological evaluation showed that 9b was a potent inhibitor for wild-type EZH2 and greatly reduced the overall levels of H3K27me3 in a concentration-dependent manner. Further study indicated that 9b could significantly induce apoptosis of SU-DHL-4 cells. These findings indicated that 9b would be an attractive lead compound for further optimization and evaluation.

Keywords: (E)-1,2-Diphenylethenem; EZH2; H3K27Me3; PRC2; SKLB1049.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Enhancer of Zeste Homolog 2 Protein / antagonists & inhibitors*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology*
  • Epigenesis, Genetic / drug effects
  • Histones / metabolism
  • Humans
  • Methylation / drug effects
  • Molecular Structure
  • Stilbenes / chemical synthesis
  • Stilbenes / pharmacology*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Histones
  • Stilbenes
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein