Identification of novel EZH2 inhibitors through pharmacophore-based virtual screening and biological assays

Bioorg Med Chem Lett. 2016 Aug 1;26(15):3813-7. doi: 10.1016/j.bmcl.2016.05.018. Epub 2016 May 30.


Polycomb repressive complex 2 (PRC2) acts as a primary writer for di- and tri-methylation of histone H3 at lysine 27. This protein plays an essential role in silencing gene expression. Enhancer of zeste 2 (EZH2), the catalytic subunit of PRC2, is considered as a promising therapeutic target for cancer. GSK126, a specific inhibitor of EZH2, is undergoing phase I trials for hypermethylation-related cancers. In addition, many derivatives of GSK126 are also commonly used in laboratory investigations. However, studies on the mechanism and drug development of EZH2 are limited by the absence of structural diversity of these inhibitors because they share similar SAM-like scaffolds. In this study, we generated a pharmacophore model based on reported EZH2 inhibitors and performed in silico screenings. Experimental validations led to the identification of two novel EZH2 inhibitors, DCE_42 and DCE_254, with IC50 values of 23 and 11μM, respectively. They also displayed significant anti-proliferation activity against lymphoma cell lines. Thus, we discovered potent EZH2 inhibitors with novel scaffold using combined in silico screening and experimental study. Results from this study can also guide further development of novel specific EZH2 inhibitors.

Keywords: Computational drug design; EZH2; Epigenetics; PRC2; Pharmacophore-based virtual screening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


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