Purity: > 98%
PD98059 is a non-ATP competitive MEK inhibitor with IC50 of 2 μM, specifically inhibits MEK-1-mediated activation of MAPK; does not directly inhibit ERK1 or ERK2. PD98059 inhibits either basal MEK1 or a partially activated MEK produced by mutation of serine at residues 218 and 222 to glutamate (MEK-2E) with IC50 of 2 μM. PD98059 does not inhibit the MAPK homologues JNK and P38. PD98059 is highly selective against MEK, as it does not inhibit a number of other kinase activities including Raf kinase, cAMP-dependent kinase, protein kinase C, v-Src, epidermal growth factor (EGF) receptor kinase, insulin receptor kinase, PDGF receptor kinase, and phosphatidylinositol 3-kinase. PD98059 inhibits PDGF-stimulated activation of MAPK and thymidine incorporation into 3T3 cells with IC50 of ~10 μM and ~7 μM, respectively . PD98059 potently prevents the activation of MEK1 by Raf or MEK kinase with IC50 of 4 μM, and weakly inhibits the activation of MEK2 by Raf with IC50 of 50 μM. PD98059 does not inhibit the activation of MEK homologues MKK4 and RK kinase that participate in stress and interleukin-1-stimulated kinase cascades in KB and PC12 cells, and the activation of p70 S6 kinase by insulin or epidermal growth factor in Swiss 3T3 cells.
1. Clin Exp Pharmacol Physiol. 2003 Apr;30(4):273-7.
The p42/44mitogen-activated protein kinase inhibitor PD 98059, but not U 0126,
increases a K+ current in cardiomyocytes.
Aimond F(1), Fauconnier J, Donadille D, Vassort G.
(1)INSERM U-390, Physiopathologie Cardiovasculaire, IFR No. 3, Montpellier,
1. The effects of the mitogen-activated protein kinase (MAPK) inhibitors PD 98059
and U 0126, useful tools to investigate MAPK involvement in intracellular signal
transduction pathways, were assessed on cardiomyocytes. 2. In rat freshly
isolated ventricular myocytes, under current-clamp conditions, PD 98059 (40 micro
mol/L) shortened the action potential. Under whole-cell patch-clamp, this
compound slowly induced a fast activating sustained outward K+ current that was
sensitive to 1 mmol/L Ba2+, 100 micro mol/L Gd3+, 3 mmol/L 4-aminopyridine and
100 micro mol/L tetracain. The PD 98059-induced current was prevented by 40 micro
mol/L AACOCF3, a cytosolic phospholipase A2 inhibitor. 3. U 0126 (1 micro mol/L),
a recently developed highly potent p42/44 MAPK inhibitor, did not alter K+
currents. 4. PD 98059, but not U 0126, increased arachidonic acid content,
probably as a consequence of its reported cyclo-oxygenase inhibitory effect. 5.
These observations indicate that PD 98059 activates a TREK-1 like current. Thus,
this MAPK inhibitor has to be used with caution because alterations in cell
metabolism can be secondary to changes in electrophysiological behaviour.
2. FEBS Lett. 1998 Sep 4;434(3):241-4.
Pervanadate-triggered MAP kinase activation and cell proliferation are not
sensitive to PD 98059. Evidence for stimulus-dependent differential PD 98059
Krady MM(1), Malviya AN, Dupont JL.
(1)Laboratoire de Neurobiologie Moléculaire des Interactions Cellulaires, CNRS
UPR 416, Strasbourg, France.
A tight and stable complex with corresponding protein kinases and phosphatases
establishes coupling between activators and inactivators. One such example is
emerging from the studies of the Ras-dependent MAP kinase cascade signaling
pathway. Pervanadate, a potent inhibitor of protein tyrosine phosphatase,
stimulates MAP kinase and elicits cell proliferation in cultured mouse
fibroblasts which is insensitive to PD 98059, the major inhibitor of upstream
MEK, whereas serum- or TPA-triggered proliferation is sensitive to PD 98059. It
is suggested that imbalanced coordination between protein kinase and protein
phosphatase determines the cellular responses such as cell proliferation. The PD
98059-insensitive cell proliferation upon protein tyrosine phosphatase inhibition
is attributed to a MEK bypass pathway.
3. Exp Cell Res. 1998 May 25;241(1):12-22.
PD 98059 prevents establishment of the spindle assembly checkpoint and inhibits
the G2-M transition in meiotic but not mitotic cell cycles in Xenopus.
Cross DA(1), Smythe C.
(1)Department of Biochemistry, The University, Dundee, United Kingdom.
Most chemotherapeutic agents block DNA replication, damage DNA, or interfere with
chromosome segregation. The existence of checkpoints, which monitor these events,
indicates that mechanisms exist to avoid death when essential cellular events are
inhibited. A molecular understanding of cellular checkpoints should therefore
provide opportunities for the development of inhibitors of checkpoint controls
which may increase the potency of chemotherapeutic drugs by inducing catastrophic
cell cycle progression. The molecular dissection of cell cycle arrest points is
facilitated in the Xenopus egg/oocyte system, in which cell-free systems retain
both S/M and spindle assembly checkpoints. Members of the MAP kinase family have
been shown to play a role in the induction of G2 to M transition during oocyte
maturation and have been implicated in the maintenance of either cytostatic
factor- or spindle assembly checkpoint-induced M-phase arrest. Here, we have
examined the effects of the inhibitor of MAP kinase kinase activation, PD 98059,
on cell cycle progression in Xenopus oocytes and in cell-free extracts. This
inhibitor is highly specific for the kinase which activates the classical p42/p44
MAP kinase, having no effect on upstream activators of stress-activated protein
kinases. We have found that PD 98059 inhibits oocyte maturation, consistent with
a role for p42 MAP kinase as a rate-limiting component in the induction of
meiosis, but had no effect on the timing of G2-M transition in cell-free extracts
indicating that, unlike meiosis, p42 MAP kinase activation is not limiting for
normal mitotic M phase entry. However, we found that cytostatic factor-induced
metaphase arrest, as well as the spindle assembly checkpoint, were both abolished
in the presence of the drug. These results demonstrate that p42 MAP kinase, and
not some other member of the MAP kinase family, is responsible for both CSF- and
checkpoint-induced metaphase arrest and suggest that PD 98059 and similar agents
may have considerable therapeutic potential for the potentiation of