Discovery of EBI-907: A highly potent and orally active B-Raf(V600E) inhibitor for the treatment of melanoma and associated cancers

Bioorg Med Chem Lett. 2016 Feb 1;26(3):819-823. doi: 10.1016/j.bmcl.2015.12.086. Epub 2015 Dec 24.

Abstract

A novel series of pyrazolo[3,4-c]isoquinoline derivatives was discovered as B-Raf(V600E) inhibitors through scaffold hopping based on a literature lead PLX4720. Further SAR exploration and optimization led to the discovery of potent B-Raf(V600E) inhibitors with good oral bioavailability in rats and dogs. One of the compounds EBI-907 (13g) demonstrated excellent in vivo efficacy in B-Raf(V600E) dependent Colo-205 tumor xenograft models in mouse and is under preclinical studies for the treatment of melanoma and B-Raf(V600E) associated cancers.

Keywords: B-Raf(V600E); Cancer; Kinase; Pyrazolo[3,4-c]isoquinoline; Scaffold hopping.

MeSH terms

  • Administration, Oral
  • Animals
  • Binding Sites
  • Cell Line, Tumor
  • Dogs
  • Drug Evaluation, Preclinical
  • Half-Life
  • Humans
  • Isoquinolines / chemistry
  • Isoquinolines / pharmacokinetics
  • Isoquinolines / therapeutic use
  • Melanoma / drug therapy
  • Mice
  • Molecular Conformation
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins B-raf / metabolism
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacokinetics
  • Pyrazoles / therapeutic use
  • Rats
  • Structure-Activity Relationship
  • Transplantation, Heterologous

Substances

  • EBI-907
  • Isoquinolines
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Proto-Oncogene Proteins B-raf
  • isoquinoline