Discovery of a novel pan-RAF inhibitor with potent anti-tumor activity in preclinical models of BRAFV600E mutant cancer

Life Sci. 2017 Aug 15;183:37-44. doi: 10.1016/j.lfs.2017.06.021. Epub 2017 Jun 21.


Aims: BRAF mutations, especially BRAF V600E, are a frequent occurrence in malignant melanomas. The BRAF inhibitors are used as the care standard for BRAF-mutant metastatic melanomas. However, melanomas rapidly develop resistance to BRAF inhibitors after a median response duration of 6months, and the subsequent rapid development of cutaneous toxicity is enhanced by the paradoxical activation of CRAF. In this study, we discovered a potent and selective pan-RAF inhibitor: INU-152. The goal of this study was to investigate whether the inhibition of pan-RAF with INU-152 completely disrupts the MAPK pathway in cancer cells bearing BRAF or RAS mutations.

Main methods: Using a structure-based molecular modeling, we discovered INU-152, which is a potent and selective pan-RAF inhibitor. In kinase assays against RAF proteins, INU-152 exhibited a potent effect against RAF isoforms. INU-152 was tested for its inhibitory effect on the growth of human cancer cells bearing BRAFV600E. To study in vivo effects, INU-152 was administered using human melanoma and colorectal cancer xenograft models. To explore INU-152's potential as a prospective drug candidate, pharmacokinetic studies and toxicity tests were performed using mice.

Key findings: To inhibit and suppress paradoxical activation in mutant RAS cancer cells completely, it is important for RAF inhibitors to exhibit potent inhibitory activities against RAF isoforms.

Significance: INU-152 inhibits all RAF isoforms and inhibits MAPK pathways in mutant BRAF cells. More importantly, INU-152 exhibits minimal paradoxical pathway activation in melanoma cells with mutant RAS. INU-152 exhibits anti-tumor activities in xenograft models carrying BRAF mutations.

Keywords: BRAFV600E mutant; Colorectal cancer; Melanoma; Pan-RAF inhibitor; RAS mutant.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / toxicity
  • Cell Line, Tumor
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics
  • Female
  • Humans
  • MAP Kinase Signaling System / drug effects
  • Male
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred ICR
  • Mice, Nude
  • Mutation
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / toxicity
  • Proto-Oncogene Proteins B-raf / genetics*
  • Purines / pharmacokinetics
  • Purines / pharmacology*
  • Purines / toxicity
  • Rats
  • Rats, Sprague-Dawley
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / pharmacology*
  • Sulfonamides / toxicity
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • INU-152
  • Protein Kinase Inhibitors
  • Purines
  • Sulfonamides
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf