PD 98059

Description

PD 98059 is a noncompetitive inhibitor of the MAPK pathway. It prevents the activation of MEK by Raf or MEK kinase (a MAP3K) with an IC₅₀ value of 2-7 μM but does not inhibit Raf-activated MAP2K1. It inhibits Raf activation of MAP2K2 with an IC₅₀ value of 50 μM. PD 98059 also phosphorylates and activates AMP-activated protein kinase (AMPK) in a dose-dependent manner (EC₅₀ = 35 μM in HEK293 cells). It increases the ratios of ADP to ATP and AMP to ATP and increases phosphorylation of the AMPK target acetyl-CoA carboxylase (ACC).

Uses

PD 98059 is a selective inhibitor of MEK and blocker of MAPK.

Definition

ChEBI: A member of the class of monomethoxyflavones that is 3'-methoxyflavone bearing an additional amino substituent at position 2'

General Description

Selective, reversible, and cell-permeable inhibitor of MAP kinase kinase (MEK) that acts by inhibiting the activation of MAP kinase and subsequent phosphorylation of MAP kinase substrates. Pretreatment of PC-12 cells with PD 98059 completely blocks the 4-fold increase in MAP kinase activity produced by nerve growth factor (NGF; IC₅₀ = 2 μM); however, it has no effect on NGF-dependent tyrosine phosphorylation of the p140^trk receptor or its substrate Shc and does not block NGF-dependent activation of PI 3-kinase. Blocks LPS-induced activation of TNF-α gene expression. Inhibits cell growth and reverses the phenotype of ras-transformed BALB3T3 mouse fibroblasts and rat kidney cells. A 5 mg/ml solution of PD 98059 (Cat. No. 513001) in anhydrous DMSO is also available.

Biological Activity

Specific inhibitor of mitogen-activated protein kinase kinase (MAPKK / MEK). Acts by binding to the inactivated form of MEK, thereby preventing its phosphorylation by cRAF or MEK kinase (IC 50 = 2-7 μ M). Inhibits cell growth and proliferation in acute myelogenous leukemia (AML) cell lines; causes G 1 arrest by blocking p53-dependent p21 induction. Also available as part of the MAPK Cascade Inhibitor Tocriset™ and MAPK Inhibitor Tocriset™ .

Biochem/physiol Actions

PD 98,059 is a flavonoid and specific inhibitor of mitogen-activated protein kinase kinase (MAPKK). In mice, PD 98,059 helps to block zymosan stimulated organ dysfunction syndrome and non-septic shock. It is known to inhibit in vitro hypertrophy. PD 98,059 also induces cartilage formation in mesenchymal stromal cells.

storage

Room temperature

References

1) Alessi 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 2) Dudley et al. (1995), A synthetic inhibitor of the mitogen-activated protein kinase cascade; Proc. Natl. Acad. Sci., 92 7686 3) Hotokezaka et al. (2002) U0126 and PD98059, specific inhibitors of MEK, accelerate differentiation of RAW264.7 cells into osteoclast-like cells; J. Biol. Chem., 277 47366 4) Xiaoxia et al. (2004) BMP4 supports self-renewal of embryonic stem cells by inhibiting mitogen-activated protein kinase pathways; Proc. Natl. Acad. Sci. USA 101 6027