Targeting the Raf kinase cascade in cancer therapy--novel molecular targets and therapeutic strategies.
The mitogen-activated protein kinases (MAPKs) are a group of signal transducers with oncogenic potential in an assortment of cell types. Dysregulated signalling from any of the members of this family has been shown to result in development of human malignancies. Consequently, the collective goal of the scientific community is to inhibit aberrant signalling initiated from these molecules whilst minimising toxicity associated with such inhibition. This review covers events responsible for MAPK activation in detail, with an emphasis placed upon possible points of pharmacological intervention. A discussion addressing numerous chemotherapeutic approaches that have been developed over the previous decade for MAPK inhibition is also included. In addition, emphasis is placed upon the various arrays of kinase inhibitors, small molecule inhibitors, competitive inhibitors, nucleic acid aptamers and other molecules which have been proven effective in prevention of MAPK signalling. Finally, the potential therapeutic promise of many of these compounds is addressed in a manner that encompasses the complexities of MAPK signal transduction, in addition to concerns surrounding the development of drug resistance.
Lee
John T
JT
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA. jtl1123@mail.ecu.edu
McCubrey
James A
JA
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D016207:Cytokines / Q000502:physiology; D015195:Drug Design; D004357:Drug Synergism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D015513:Oncogene Proteins / Q000187:drug effects / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017978:Receptors, Growth Factor / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000502:physiology; D048490:raf Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
D000970:Antineoplastic Agents; D016207:Cytokines; D015513:Oncogene Proteins; D047428:Protein Kinase Inhibitors; D017978:Receptors, Growth Factor; D014157:Transcription Factors; D048490:raf Kinases