SAH derived potent and selective EZH2 inhibitors

Bioorg Med Chem Lett. 2015 Apr 1;25(7):1532-7. doi: 10.1016/j.bmcl.2015.02.017. Epub 2015 Feb 17.


A series of novel enhancer of zeste homolog 2 (EZH2) inhibitors was designed based on the chemical structure of the histone methyltransferase (HMT) inhibitor SAH (S-adenosyl-l-homocysteine). These nucleoside-based EZH2 inhibitors blocked the methylation of nucleosomes at H3K27 in biochemical assays employing both WT PRC2 complex as well as a Y641N mutant PRC2 complex. The most potent compound, 27, displayed IC50's against both complexes of 270 nM and 70 nM, respectively. To our knowledge, compound 27 is the most potent SAH-derived inhibitor of the EZH2 PRC2 complex yet identified. This compound also displayed improved potency, lipophilic efficiency (LipE), and selectivity profile against other lysine methyltransferases compared with SAH.

Keywords: EZH2; Homology model; Nucleoside; SAH.

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Design
  • Enhancer of Zeste Homolog 2 Protein
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Polycomb Repressive Complex 2 / antagonists & inhibitors*
  • S-Adenosylhomocysteine / chemical synthesis
  • S-Adenosylhomocysteine / chemistry
  • S-Adenosylhomocysteine / pharmacology*
  • Structure-Activity Relationship


  • S-Adenosylhomocysteine
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2