Raf kinase inhibitors in oncology

The importance of the MAP kinase pathway, which includes the kinases Raf, MEK1/ 2, and ERK1/ 2, for the proliferation and survival of tumor cells recently increased with the discovery of activating BRAF mutations in human tumors. Therefore, in addition to a role in controlling tumors with Ras mutations and activated growth factor receptors, inhibitors of Raf kinase may harbor therapeutic potential in tumors carrying a BRAF oncogene. A variety of agents have been discovered to interfere with Raf kinase, including antisense oligonucleotides and small molecules. These inhibitors prevent the expression of Raf protein, block Ras/ Raf interaction, or obstruct its kinase activity. Raf inhibitors that are currently undergoing clinical evaluation show promising signs of anti- cancer efficacy with a very tolerable safety profile. Clinically most advanced is the Raf inhibitor BAY 43- 9006, which recently entered phase III clinical testing. This review addresses the rationale for targeting Raf kinase and the current status of various pharmacological approaches.