Description
U-0126 is a MEK inhibitor with IC
50 values of 72 nM and 58 nM for MEK1 and MEK2, respectively. It is noncompetitive with respect adenosine triphosphate (ATP) and its phosphorylation target ERK and it shows little to no inhibition against a number of other kinases including PKC, Ab1, Raf, MEKK, ERK, JNK, MKK-3, MKK-4, MKK-6, Cdk2, and Cdk4. However, U-0126 does phosphorylate and activate AMP-activated protein kinase (AMPK) in a dose-dependent manner (EC
50 = 15 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
A chemically synthesized and highly selective inhibitor of both MEK1 and MEK2 with IC50s of 70 nM and 60 nM, respectively.
Uses
U0126 is a MEK inhibitor.
Definition
ChEBI: A dinitrile that is succinonitrile in which the methylene hydrogens at positions 2 and 3 are substituted by (2-aminophenyl)sulfanyl]methylidene groups. A potent and selective non-competitive inhibitor of MAP kinase kinase.
General Description
A potent and specific inhibitor of MEK1 (IC
50 = 72 nM) and MEK2 (IC
50 = 58 nM). The inhibition is noncompetitive with respect to MEK substrates, ATP and ERK. Has very little effect on other kinases, such as Abl, Cdk2, Cdk4, ERK, JNK, MEKK, MKK-3, MKK-4/SEK, MKK-6, PKC, and Raf. Shown to block doxazosin-induced osteoblastic differentiation. U0126 also acts as an immunosuppressant by effectively blocking IL-2 synthesis and T cell proliferation without affecting the long-term outcomes of either T cell activation or tolerance. Noncompetitive with respect to ATP. Also available in InSolution format (Cat. No. 662009.
Biological Activity
Potent and selective non-competitive inhibitor of MAP kinase kinase. Inhibits MEK-1 and MEK-2 (IC 50 values of 0.07 and 0.06 μ M respectively) with little or no effect on the activities of PKC, Abl, Raf, MEKK, ERK, JNK, MKK-3, MKK-4/SEK, MKK-6, Cdk2 or Cdk4. Centrally active following systemic administration in vivo . Also available as part of the MAPK Cascade Inhibitor Tocriset™ and MAPK Inhibitor Tocriset™ .
Biochem/physiol Actions
Primary TargetMEK1 and MEK2
Background
MEK1 and MEK2, also called MAPK or Erk kinases, are dual-specificity protein kinases that function in a mitogen activated protein kinase cascade controlling cell growth and differentiation. Activation of MEK1 and MEK2 occurs through phosphorylation of two serine residues at positions 217 and 221, located in the activation loop of subdomain VIII, by Raf-like molecules. MEK1/2 is activated by a wide variety of growth factors and cytokines and also by membrane depolarization and calcium influx. Constitutively active forms of MEK1/2 are sufficient for the transformation of NIH/3T3 cells or the differentiation of PC-12 cells. MEK activates p44 and p42 MAP kinase by phosphorylating both threonine and tyrosine residues at sites located within the activation loop of kinase subdomain VIII.
References
[1] M F FAVATA. Identification of a novel inhibitor of mitogen-activated protein kinase kinase.[J]. The Journal of Biological Chemistry, 1998, 273 29: 18623-18632. DOI:
10.1074/jbc.273.29.18623[2] SEIGO MIYOSHI. Antitumor activity of MEK and PI3K inhibitors against malignant pleural mesothelioma cells in vitro and in vivo.[J]. International journal of oncology, 2012, 41 2: 449-456. DOI:
10.3892/ijo.2012.1462[3] KATIE L. PRICOLA. Interleukin-6 maintains bone marrow-derived mesenchymal stem cell stemness by an ERK1/2-dependent mechanism†‡[J]. Journal of cellular biochemistry, 2009, 108 3: 577-588. DOI:
10.1002/jcb.22289
