title: Potent and selective mitogen-activated protein kinase kinase (MEK) 1,2 inhibitors. 1. 4-(4-bromo-2-fluorophenylamino)-1- methylpyridin-2(1H)-ones.
abstract: The role of MEK 1,2 in cancer tumorgenesis has been clearly demonstrated preclinically, and two selective inhibitors are currently undergoing clinical evaluation to determine their role in the human disease. We have discovered 4-(4-bromo-2-fluorophenylamino)-1-methylpyridin-2(1H)-ones as a new class of ATP noncompetitive MEK inhibitors. These inhibitors exhibit excellent cellular potency and good pharmacokinetic properties and have demonstrated the ability to inhibit ERK phosphorylation in HT-29 tumors from mouse xenograft studies.
authors.affiliation: Array BioPharma, Boulder, Colorado 80301, USA. ewallace@arraybiopharma.com
authors.forename: Eli M
authors.initials: EM
authors.lastname: Wallace
authors.forename: Joseph
authors.initials: J
authors.lastname: Lyssikatos
authors.forename: James F
authors.initials: JF
authors.lastname: Blake
authors.forename: Jeongbeob
authors.initials: J
authors.lastname: Seo
authors.forename: Hong Woon
authors.initials: HW
authors.lastname: Yang
authors.forename: Tammie C
authors.initials: TC
authors.lastname: Yeh
authors.forename: Michele
authors.initials: M
authors.lastname: Perrier
authors.forename: Heidi
authors.initials: H
authors.lastname: Jarski
authors.forename: Vivienne
authors.initials: V
authors.lastname: Marsh
authors.forename: Gregory
authors.initials: G
authors.lastname: Poch
authors.forename: Michelle Goyette
authors.initials: MG
authors.lastname: Livingston
authors.forename: Jennifer
authors.initials: J
authors.lastname: Otten
authors.forename: Gary
authors.initials: G
authors.lastname: Hingorani
authors.forename: Rich
authors.initials: R
authors.lastname: Woessner
authors.forename: Patrice
authors.initials: P
authors.lastname: Lee
authors.forename: James
authors.initials: J
authors.lastname: Winkler
authors.forename: Kevin
authors.initials: K
authors.lastname: Koch
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D002470:Cell Survival / Q000187:drug effects; D004355:Drug Stability; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors*; D051379:Mice; D010766:Phosphorylation; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D011725:Pyridines; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2