Discovery of highly selective CRAF inhibitors, 3-carboxamido-2H-indazole-6-arylamide: In silico FBLD design, synthesis and evaluation

Bioorg Med Chem Lett. 2016 Feb 15;26(4):1188-92. doi: 10.1016/j.bmcl.2016.01.037. Epub 2016 Jan 16.

Abstract

The recent success of vemurafenib shows the importance of selective BRAF V600E inhibition in melanoma. However, paradoxical activation by structurally diverse ATP-competitive RAF kinase inhibitors strongly suggests that selective CRAF inhibitors, not BRAF inhibitors, would be ideal for some Ras mutation cancer treatment. In this respect, we approached designing selective CRAF inhibitors starting from in silico fragment screening and synthesized a 3-carboxamido-2H-indazole-6-arylamide scaffold. Most of the compounds showed potent antiproliferative activity against the WM3629 melanoma cell line and the most promising compound, compound 10d, was found to be a potent and selective CRAF inhibitor with an IC50 value of 38.6 nM, which shows greater than 270-fold selectivity over BRAF kinase (9.45 μM).

Keywords: BRAF V600E; CRAF; Melanoma; Selectivity.

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry*
  • Amides / pharmacology
  • Binding Sites
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Design*
  • Humans
  • Indazoles / chemistry*
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / toxicity
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-raf / metabolism

Substances

  • Amides
  • Indazoles
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-raf