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J Biol Chem, Vol. 273, Issue 29, 18623-18632, July 17, 1998
From the The compound U0126
(1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene) was
identified as an inhibitor of AP-1 transactivation in a cell-based
reporter assay. U0126 was also shown to inhibit endogenous promoters
containing AP-1 response elements but did not affect genes lacking an
AP-1 response element in their promoters. These effects of U0126 result
from direct inhibition of the mitogen-activated protein kinase kinase
family members, MEK-1 and MEK-2. Inhibition is selective for MEK-1 and
-2, as U0126 shows little, if any, effect on the kinase activities of
protein kinase C, Abl, Raf, MEKK, ERK, JNK, MKK-3, MKK-4/SEK, MKK-6,
Cdk2, or Cdk4. Comparative kinetic analysis of U0126 and the MEK
inhibitor PD098059 (Dudley, D. T., Pang, L., Decker, S. J.,
Bridges, A. J., and Saltiel, A. R. (1995) Proc. Natl.
Acad. Sci U. S. A. 92, 7686-7689) demonstrates that U0126 and
PD098059 are noncompetitive inhibitors with respect to both MEK
substrates, ATP and ERK. We further demonstrate that the two compounds
bind to
Identification of a Novel Inhibitor of Mitogen-activated Protein
Kinase Kinase
,,,,,,,, and
Inflammatory Diseases Research,
¶ Chemical Enzymology and § Chemical and Physical
Sciences, The DuPont Merck Research Laboratories,
Wilmington, Delaware 19880-0400
N3-S218E/S222D MEK in a mutually exclusive fashion,
suggesting that they may share a common or overlapping binding site(s).
Quantitative evaluation of the steady state kinetics of MEK inhibition
by these compounds reveals that U0126 has approximately 100-fold higher
affinity for N3-S218E/S222D MEK than does PD098059. We further
tested the effects of these compounds on the activity of wild type MEK
isolated after activation from stimulated cells. Surprisingly, we
observe a significant diminution in affinity of both compounds for wild
type MEK as compared with the N3-S218E/S222D mutant enzyme. These
results suggest that the affinity of both compounds is mediated by
subtle conformational differences between the two activated MEK forms.
The MEK affinity of U0126, its selectivity for MEK over other kinases,
and its cellular efficacy suggest that this compound will serve as a
powerful tool for in vitro and cellular investigations of
mitogen-activated protein kinase-mediated signal transduction.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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