Discovery and optimization of a novel series of potent mutant B-Raf(V600E) selective kinase inhibitors

J Med Chem. 2013 Mar 14;56(5):1996-2015. doi: 10.1021/jm301658d. Epub 2013 Feb 27.


B-Raf represents an attractive target for anticancer therapy and the development of small molecule B-Raf inhibitors has delivered new therapies for metastatic melanoma patients. We have discovered a novel class of small molecules that inhibit mutant B-Raf(V600E) kinase activity both in vitro and in vivo. Investigations into the structure-activity relationships of the series are presented along with efforts to improve upon the cellular potency, solubility, and pharmacokinetic profile. Compounds selectively inhibited B-Raf(V600E) in vitro and showed preferential antiproliferative activity in mutant B-Raf(V600E) cell lines and exhibited selectivity in a kinase panel against other kinases. Examples from this series inhibit growth of a B-Raf(V600E) A375 xenograft in vivo at a well-tolerated dose. In addition, aminoquinazolines described herein were shown to display pERK elevation in nonmutant B-Raf cell lines in vitro.

MeSH terms

  • Animals
  • Humans
  • Male
  • Melanoma / drug therapy
  • Mice
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins B-raf / genetics
  • Quinazolines / chemical synthesis*
  • Quinazolines / pharmacokinetics
  • Quinazolines / pharmacology
  • Rats
  • Structure-Activity Relationship


  • Protein Kinase Inhibitors
  • Quinazolines
  • Proto-Oncogene Proteins B-raf

Associated data

  • PDB/4BB4
  • PDB/4H58