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How does the MEK inhibitor U0126 compare to PD098059 in activity?
Recently, Promega introduced U0126 (Cat.# V1121) as a novel
inhibitor of MEK. Like PD098059, this compound inhibits the activation of MAPK. MAPK is
phosphorylated and activated by both MEK1 and MEK2. However, whereas PD098059 is a more
potent inhibitor of MEK1 than MEK2 in vitro (IC50 of 4µM versus 50µM,
repsectively), U0126 inhibits both MEK1 and MEK2 in vitro with comparable IC50
values (72nM and 58nM, respectively) (1-3).
Both compounds act as noncompetitive inhibitors of MEK1 (3), but the binding affinity
of U0126 for MEK1 is 20 to 40-fold higher than that of PD098059 (4). The mode of action of
U0126 is also slightly different from that of PD098059 in that the latter inhibitor is
presumed to exert its effect by inhibiting phosphorylation, and hence activation, of MEK
by upstream kinases (2). U0126, on the other hand, is capable of inhibiting MEK that has
already been activated by phosphorylation (3). Both inhibitors are capable of blocking
MAPK activation by MEK in intact cells with U0126 being effective over the concentration
range of 10-20µM and PD098059 over 10-100µM, depending on the cell type being studied.
References
- Dudley, D.T. et al. (1995) A synthetic inhibitor of the mitogen-activated
protein kinase cascade. Proc. Natl. Acad. Sci. USA 92, 7686.
- Alessi, D.R. et al. (1995) PD 098059 is a specific inhibitor of the activation
of mitogen-activated protein kinase kinase in vitro and in vivo. J. Biol. Chem. 270,
27489.
- Favata, M.F. et al. (1998) Identification of a novel inhibitor of
mitogen-activated protein kinase kinase. J. Biol. Chem. 273,
18623.
- Mansour, S.J. et al. (1996) Interdependent domains controlling the enzymatic
activity of mitogen-activated protein kinase kinase 1. Biochemistry 35,
15529.
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