Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity

BRAF(V600E) is the most frequent oncogenic protein kinase mutation known. Furthermore, inhibitors targeting "active" protein kinases have demonstrated significant utility in the therapeutic repertoire against cancer. Therefore, we pursued the development of specific kinase inhibitors targeting B-Raf, and the V600E allele in particular. By using a structure-guided discovery approach, a potent and selective inhibitor of active B-Raf has been discovered. PLX4720, a 7-azaindole derivative that inhibits B-Raf(V600E) with an IC(50) of 13 nM, defines a class of kinase inhibitor with marked selectivity in both biochemical and cellular assays. PLX4720 preferentially inhibits the active B-Raf(V600E) kinase compared with…

• UD
  U.S. Department of Energy

  Awards: DE-AC03-76SF00515, AC03-76SF00098, 76SF00515, DE-AC03-76SF00098, DE-AC03
• NI
  National Institutes of Health

  Award: DE-AC03-76SF00098
• BE
  Basic Energy Sciences

  Awards: AC03-76SF00098, DE-AC03-76SF00098, 76SF00515