title: A synthetic inhibitor of the mitogen-activated protein kinase cascade.
abstract: Treatment of cells with a variety of growth factors triggers a phosphorylation cascade that leads to activation of mitogen-activated protein kinases (MAPKs, also called extracellular signal-regulated kinases, or ERKs). We have identified a synthetic inhibitor of the MAPK pathway. PD 098059 [2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one] selectively inhibited the MAPK-activating enzyme, MAPK/ERK kinase (MEK), without significant inhibitory activity of MAPK itself. Inhibition of MEK by PD 098059 prevented activation of MAPK and subsequent phosphorylation of MAPK substrates both in vitro and in intact cells. Moreover, PD 098059 inhibited stimulation of cell growth and reversed the phenotype of ras-transformed BALB 3T3 mouse fibroblasts and rat kidney cells. These results indicate that the MAPK pathway is essential for growth and maintenance of the ras-transformed phenotype. Further, PD 098059 is an invaluable tool that will help elucidate the role of the MAPK cascade in a variety of biological settings.
authors.affiliation: Department of Signal Transduction, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Co., Ann Arbor, MI 48105, USA.
authors.forename: D T
authors.initials: DT
authors.lastname: Dudley
authors.forename: L
authors.initials: L
authors.lastname: Pang
authors.forename: S J
authors.initials: SJ
authors.lastname: Decker
authors.forename: A J
authors.initials: AJ
authors.lastname: Bridges
authors.forename: A R
authors.initials: AR
authors.lastname: Saltiel
mesh_terms: D016475:3T3 Cells; D000409:Alanine; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008239:Lysine; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000302:isolation & purification / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D005419:Flavonoids; D008869:Microtubule-Associated Proteins; D011993:Recombinant Fusion Proteins; D005982:Glutathione Transferase; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D008239:Lysine; D000409:Alanine; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D013936:Thymidine