Development of anticancer drugs targeting the MAP kinase pathway.
Since the discovery of the role of ras oncogenes in tumorigenesis, we have witnessed an explosion of research in the signal transduction area. In the quest to understand how Ras transmits extracellular growth signals, the MAP kinase (MAPK) pathway has emerged as the crucial route between membrane-bound Ras and the nucleus. The MAPK pathway encompasses a cascade of phosphorylation events involving three key kinases, namely Raf, MEK (MAP kinase kinase) and ERK (MAP kinase). This kinase cascade presents novel opportunities for the development of new cancer therapies designed to be less toxic than conventional chemotherapeutic drugs. Furthermore, as a signal transduction-based approach to cancer treatment, inhibition of any one of these targets has the potential for translational pharmacodynamic evaluation of target suppression. The rationale for targeting the MAP kinase pathway will be reviewed here along with a discussion of various pharmacological approaches and the promise they hold for a new generation of anticancer drugs.
Sebolt-Leopold
J S
JS
Pfizer Global Research and Development, Ann Arbor Laboratories, Michigan 48105, USA.
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D016503:Drug Delivery Systems; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005544:Forecasting; D006801:Humans; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors
C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; C482128:MAP2K2 protein, human; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases