MEK inhibitors: the chemistry and biological activity of U0126, its analogs, and cyclization products.
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.
Duncia
J V
JV
DuPont Pharmaceuticals Company, Chemical and Physical Sciences Department, Wilmington, DE 19880, USA.
Santella
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JB
Higley
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CA
Pitts
W J
WJ
Wityak
J
J
Frietze
W E
WE
Rankin
F W
FW
Sun
J H
JH
Earl
R A
RA
Tabaka
A C
AC
Teleha
C A
CA
Blom
K F
KF
Favata
M F
MF
Manos
E J
EJ
Daulerio
A J
AJ
Stradley
D A
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Horiuchi
K
K
Copeland
R A
RA
Scherle
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Trzaskos
J M
JM
Magolda
R L
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Trainor
G L
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Wexler
R R
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Hobbs
F W
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Olson
R E
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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
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