PLX-4032, a small-molecule B-Raf inhibitor for the potential treatment of malignant melanoma

Curr Opin Investig Drugs. 2010 Jun;11(6):699-706.


PLX-4032 is a small-molecule, orally available B-Raf kinase inhibitor being developed by Plexxikon Inc and Hoffman-La Roche Ltd for the treatment of cancers harboring activating BRAF mutations. The primary focus of development is in melanoma (> 50% harbor activating BRAF mutations) with other solid tumors, such as colorectal carcinoma (> 10% harbor BRAF mutations), also under investigation. Purified kinase assays have demonstrated that PLX-4032 and its related analogs are highly potent inhibitors of B-Raf activity, with 3-fold selectivity for the V600E mutation over the wild-type kinase. In preclinical models, PLX-4032 and its analogs inhibited the growth of BRAFV600E-positive melanoma cell lines both in vitro and in vivo. In phase I clinical trials, PLX-4032 was well tolerated and objective responses were observed in several patients with BRAFV600E-positive tumors. Responses correlated well with inhibition of intratumoral phospho-ERK and cell proliferation, and reductions in fluorodeoxyglucose uptake on PET scanning. A preliminary analysis of this phase I data suggested that progression-free survival was approximately 7 months, and phase II and III clinical trials are now underway. These studies provide the proof-of-concept for B-Raf as a therapeutic target in melanoma.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Humans
  • Indoles / adverse effects
  • Indoles / pharmacokinetics
  • Indoles / pharmacology
  • Indoles / therapeutic use*
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Molecular Targeted Therapy*
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins B-raf / genetics
  • Sulfonamides / adverse effects
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use*
  • Vemurafenib


  • Indoles
  • Protein Kinase Inhibitors
  • Sulfonamides
  • Vemurafenib
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf