title: Synthesis and evaluation of 4-anilino-6,7-dialkoxy-3-quinolinecarbonitriles as inhibitors of kinases of the Ras-MAPK signaling cascade.
abstract: 4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)]anilino-6,7-diethoxy-3-quinolinecarbonitrile (3) was identified as a MEK1 kinase inhibitor with exceptional activity against LoVo cells. The structure-activity relationships of the C-4 aniline substituents were explored, and water-solubilizing groups were added at the C-7 position to improve physical properties. Secondary cellular assays revealed that a compound possessing the appropriate aniline substituents inhibited MEK1 as well as MAPK phosphorylation, thereby acting as a dual inhibitor of the Ras-MAPK signaling cascade.
authors.affiliation: Chemical Sciences, Wyeth Research, Pearl River, NY 10965, USA. berger@wyeth.com
authors.forename: Dan
authors.initials: D
authors.lastname: Berger
authors.forename: Minu
authors.initials: M
authors.lastname: Dutia
authors.forename: Dennis
authors.initials: D
authors.lastname: Powell
authors.forename: Biqi
authors.initials: B
authors.lastname: Wu
authors.forename: Allan
authors.initials: A
authors.lastname: Wissner
authors.forename: Diane H
authors.initials: DH
authors.lastname: Boschelli
authors.forename: M Brawner
authors.initials: MB
authors.lastname: Floyd
authors.forename: Nan
authors.initials: N
authors.lastname: Zhang
authors.forename: Nancy
authors.initials: N
authors.lastname: Torres
authors.forename: Jeremy
authors.initials: J
authors.lastname: Levin
authors.forename: Xuemei
authors.initials: X
authors.lastname: Du
authors.forename: Donald
authors.initials: D
authors.lastname: Wojciechowicz
authors.forename: Carolyn
authors.initials: C
authors.lastname: Discafani
authors.forename: Constance
authors.initials: C
authors.lastname: Kohler
authors.forename: Steven C
authors.initials: SC
authors.lastname: Kim
authors.forename: Larry R
authors.initials: LR
authors.lastname: Feldberg
authors.forename: Karen
authors.initials: K
authors.lastname: Collins
authors.forename: Robert
authors.initials: R
authors.lastname: Mallon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D048369:MAP Kinase Kinase 1; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009570:Nitriles / Q000138:chemical synthesis* / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009570:Nitriles; D011804:Quinolines; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases