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.
Strumberg
Dirk
D
Department of Internal Medicine and Medical Oncology, West German Cancer Center, University of Essen, Germany. dirk.strumberg@uni-essen.de
Seeber
Siegfried
S
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000627:therapeutic use*; D000077157:Sorafenib; D048490:raf Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; D048490:raf Kinases