Discovery of EBI-1051: A novel and orally efficacious MEK inhibitor with benzofuran scaffold

Bioorg Med Chem. 2018 Feb 1;26(3):581-589. doi: 10.1016/j.bmc.2017.12.019. Epub 2017 Dec 20.

Abstract

A novel series of benzodihydrofuran derivatives was developed as potent MEK inhibitors through scaffold hopping based on known clinical compounds. Further SAR exploration and optimization led to another benzofuran series with good oral bioavailability in rats. One of the compounds EBI-1051 (28d) demonstrated excellent in vivo efficacy in colo-205 tumor xenograft models in mouse and is suitable for pre-clinical development studies for the treatment of melanoma and MEK associated cancers. Compared to AZD6244, EBI-1051 showed superior potency in some cancer cell lines such as colon-205, A549 and MDA-MB-231.

Keywords: Benzofuran; Kinase; MEK inhibitors; Scaffold hopping.

MeSH terms

  • Administration, Oral
  • Animals
  • Benzofurans / administration & dosage
  • Benzofurans / chemistry*
  • Benzofurans / pharmacokinetics
  • Benzofurans / pharmacology*
  • Benzofurans / toxicity
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Evaluation, Preclinical
  • Enzyme Activation / drug effects
  • Humans
  • Mice
  • Mice, Nude
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Neoplasms / drug therapy
  • Neoplasms / pathology
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Transplantation, Heterologous

Substances

  • Benzofurans
  • EBI-1051
  • Protein Kinase Inhibitors
  • Mitogen-Activated Protein Kinase Kinases
  • benzofuran