Discovery, design, and synthesis of indole-based EZH2 inhibitors

Bioorg Med Chem Lett. 2015 Sep 1;25(17):3644-9. doi: 10.1016/j.bmcl.2015.06.056. Epub 2015 Jun 19.

Abstract

The discovery and optimization of a series of small molecule EZH2 inhibitors is described. Starting from dimethylpyridone HTS hit (2), a series of indole-based EZH2 inhibitors were identified. Biochemical potency and microsomal stability were optimized during these studies and afforded compound 22. This compound demonstrates nanomolar levels of biochemical potency (IC50=0.002 μM), cellular potency (EC50=0.080 μM), and afforded tumor regression when dosed (200 mpk SC BID) in an EZH2 dependent tumor xenograft model.

Keywords: EZH2; Epigenetics; Histone methyltransferase; PRC2; Pyridone.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Chemistry Techniques, Synthetic
  • Drug Design
  • Drug Discovery
  • Drug Screening Assays, Antitumor
  • Drug Stability
  • Enhancer of Zeste Homolog 2 Protein
  • HeLa Cells / drug effects
  • Humans
  • Indoles / chemistry*
  • Inhibitory Concentration 50
  • Mice
  • Molecular Targeted Therapy / methods
  • Polycomb Repressive Complex 2 / antagonists & inhibitors*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Structure-Activity Relationship
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Indoles
  • Small Molecule Libraries
  • indole
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2