Design, synthesis and evaluation of derivatives based on pyrimidine scaffold as potent Pan-Raf inhibitors to overcome resistance

Eur J Med Chem. 2017 Apr 21;130:86-106. doi: 10.1016/j.ejmech.2017.02.041. Epub 2017 Feb 21.


Simutaneous targeting all Raf isoforms offers the prospect of enhanced efficacy as well as reduced potential for resistance. Described herein is the discovery and characterization of a series of pyrimidine scaffold with DFG-out conformation as potent Pan-Raf inhibitors. Among them, I-41 with excellent Pan-Raf potency demonstrates inhibitory activity against BRafWT phenotypic melanoma and BRafV600E phenotypic colon cells. The western blot results for the Erk inhibition in human melanoma SK-Mel-2 cell lines showed I-41 inhibited the proliferation of SK-Mel-2 cell lines without paradoxical activation of Erk, which supported I-41 may become a good candidate compound to overcome the resistance of melanoma against the current BRafV600E inhibitor therapy. I-41 also have a favorable pharmacokinetic profile in rat. Synthesis, SAR, lead selection, and evaluation of the key compounds studies are described.

Keywords: PK; Pan-Raf inhibitors; Pyrimidine scaffold; Resistance.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Design
  • Drug Resistance, Neoplasm / drug effects*
  • Humans
  • Melanoma / drug therapy
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Rats
  • raf Kinases / antagonists & inhibitors*


  • Protein Kinase Inhibitors
  • Pyrimidines
  • raf Kinases