title: MEK inhibitors: the chemistry and biological activity of U0126, its analogs, and cyclization products.
abstract: In search of antiinflammatory drugs with a new mechanism of action, U0126 was found to functionally antagonize AP-1 transcriptional activity via noncompetitive inhibition of the dual specificity kinase MEK with an IC50 of 0.07 microM for MEK 1 and 0.06 microM for MEK 2. U0126 can undergo isomerization and cyclization reactions to form a variety of products, both chemically and in vivo, all of which exhibit less affinity for MEK and lower inhibition of AP-1 activity than parent, U0126.
authors.affiliation: DuPont Pharmaceuticals Company, Chemical and Physical Sciences Department, Wilmington, DE 19880, USA.
authors.forename: J V
authors.initials: JV
authors.lastname: Duncia
authors.forename: J B
authors.initials: JB
authors.lastname: Santella
authors.forename: C A
authors.initials: CA
authors.lastname: Higley
authors.forename: W J
authors.initials: WJ
authors.lastname: Pitts
authors.forename: J
authors.initials: J
authors.lastname: Wityak
authors.forename: W E
authors.initials: WE
authors.lastname: Frietze
authors.forename: F W
authors.initials: FW
authors.lastname: Rankin
authors.forename: J H
authors.initials: JH
authors.lastname: Sun
authors.forename: R A
authors.initials: RA
authors.lastname: Earl
authors.forename: A C
authors.initials: AC
authors.lastname: Tabaka
authors.forename: C A
authors.initials: CA
authors.lastname: Teleha
authors.forename: K F
authors.initials: KF
authors.lastname: Blom
authors.forename: M F
authors.initials: MF
authors.lastname: Favata
authors.forename: E J
authors.initials: EJ
authors.lastname: Manos
authors.forename: A J
authors.initials: AJ
authors.lastname: Daulerio
authors.forename: D A
authors.initials: DA
authors.lastname: Stradley
authors.forename: K
authors.initials: K
authors.lastname: Horiuchi
authors.forename: R A
authors.initials: RA
authors.lastname: Copeland
authors.forename: P A
authors.initials: PA
authors.lastname: Scherle
authors.forename: J M
authors.initials: JM
authors.lastname: Trzaskos
authors.forename: R L
authors.initials: RL
authors.lastname: Magolda
authors.forename: G L
authors.initials: GL
authors.lastname: Trainor
authors.forename: R R
authors.initials: RR
authors.lastname: Wexler
authors.forename: F W
authors.initials: FW
authors.lastname: Hobbs
authors.forename: R E
authors.initials: RE
authors.lastname: Olson
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001711:Biotransformation; D002070:Butadienes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D003500:Cyclization; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009570:Nitriles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors
chemical_list: D000893:Anti-Inflammatory Agents; D002070:Butadienes; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D009570:Nitriles; D018808:Transcription Factor AP-1; C113580:U 0126; D017346:Protein Serine-Threonine Kinases