U0126: THE MOST POTENT MEK INHIBITOR

by Selleckchem | Mar 18 2012

The MAPK pathways

In ever cells life span there are circumstances when the cell is placed in a stressful situation, such toxic shock, injury to the surrounding tissue or old age. In such circumstances the cells must react either to die or to live and grow. The regulation of this process is the responsibility of the “Mitogen-activated protein kinases (MAPK)”. The MAP kinases are involved in a broad spectrum of processes covering proliferation (mitosis), apoptosis, cell migration/motility and gene expression. The MAP kinases are located in the cell membrane and on receipt of an external extracellular signal any one of three pathways can be stimulated, these are the ERK, JNK or the P38MAPK pathways [1]. The JNK and P38MAPK pathways are stress related signals while the ERK pathway is the proliferation or differentiation pathway. The MAP kinases are active with the phosphorylation of the tyrosine and threonine residues but this is controlled a initial MAP kinase cascade; MAP kinase kinase kinase (MAP3K) will phosphorylate MAP kinase kinase (MAP2K) which in turn phosphorylates MAPK and activates one of the three pathways [2-4]. Diseases of the cellular mechanisms are usually the uncontrolled growth (proliferation), unregulated transition of one cell type to another (differentiation) or disruption of apoptotic processes. It has been discovered that the MAPK cascades are not in total control of the downstream cellular processes possible due to abnormalities in genetic sequencing [5]. Inhibition of MARK’s or their pre-cursors is difficult in that the downstream effect usually cannot be predicted, for example it could be proliferation or apoptotic effects seen since the pathways trigger both. Hence a inhibitor to effectively change an abnormal up or down regulation of these pathway should target further downstream. U0126 MEK1 inhibitor is a small molecule that inhibits further downstream of the ERK pathway [6-8]. This pathway consists of RAS/RAF/MEK/ERK cascade and U0126 inhibits both the Raf activation of MEK1 and MEK1’s subsequent activation of ERK 1/2.

U0126-EtOH Chemical Structure

U0126: Properties and Availability

U0126 was introduced by Promega Corporation in combination with Du Pont Pharmacuticals and is used extensively in research into the activity of the MAPK pathways.U0126 has a structure based on a substituted mercapto-butadiene. U0126 mechanism of action is to inhibit MEK1’s ability to catalyses the phosphorylation of ERK 1/2. U0126 solubility in water is not listed but U0126 is soluble in DMSO to a maximum concentration of 100 mM. U0126 stability is listed for its powdered form and this can be stored for upwards of 2 years if kept at +4 or below under desiccated conditions. Also recommended is that all powders and stock solution be protected from light. Researchers can buy U0126 from a variety of U0126 suppliers although U0126 price is dependent on the supplier. U0126 price of a 25 mg vial can range from $71 up to $500; researchers are advised to shop very carefully for this product.

U0126: Its preclinical research role

Uniquely U0126 does not competitively bind to the ATP domain with ATP onto the MER1 kinase. Instead U0126 inhibits MEK1 by direct action on its catalytic properties, hence U0126 can inhibit abnormally activated MEK1 whereas other inhibitors of MEK1 only inhibit it activation. Due to this unique mode of action U0126 has been investigated intensively in terms of its specificity and its mechanism of action in a variety of diseases. In addition to its use as an inhibitor for research into mechanistic aspects U0126 has been demonstrated to have apoptotic properties of its own in NSCLC [9], breast cancer [10], hepatocellular carcinoma [11] and myeloid leukemia [12]. U0126 has been demonstrate to be more active against the active mutated MEK1 than the wild type version [13] which might have significance in cancer chemotherapy. The prospect of a U0126 clinical trial is remote but the molecular structure could serve as a basis for future molecules which could have therapeutic effects.

References

1. Wada T, Penninger JM. Mitogen-activated protein kinases in apoptosis regulation. Oncogene 2004; 23(16):2838-2849.

2. Jeuken JW, Wesseling P. MAPK pathway activation through BRAF gene fusion in pilocytic astrocytomas; a novel oncogenic fusion gene with diagnostic, prognostic, and therapeutic potential. J Pathol 2010; 222(4):324-328.

3. Tatevossian RG, Lawson AR et al. MAPK pathway activation and the origins of pediatric low-grade astrocytomas. J Cell Physiol 2010; 222(3):509-514.

4. Forshew T, Tatevossian RG et al. Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas. J Pathol 2009; 218(2):172-181.

5. Jeuken J, van den Broecke C et al. RAS/RAF pathway activation in gliomas: the result of copy number gains rather than activating mutations. Acta Neuropathol 2007; 114(2):121-133.

6. Wang ZQ, Chen XC et al. U0126 prevents ERK pathway phosphorylation and interleukin-1beta mRNA production after cerebral ischemia. Chin Med Sci J 2004; 19(4):270-275.

7. Fukazawa H, Uehara Y. U0126 reverses Ki-ras-mediated transformation by blocking both mitogen-activated protein kinase and p70 S6 kinase pathways. Cancer Res 2000; 60(8):2104-2107.

8. Ge X, Fu YM et al. U0126, a mitogen-activated protein kinase kinase inhibitor, inhibits the invasion of human A375 melanoma cells. Cancer Lett 2002; 179(2):133-140.

9. Zou ZQ, Zhang LN et al. The novel dual PI3K/mTOR inhibitor GDC-0941 synergizes with the MEK inhibitor U0126 in non-small cell lung cancer cells. Mol Med Report 2012; 5(2):503-508.

10. Yacoub A, Han SI et al. Sequence dependent exposure of mammary carcinoma cells to Taxotere and the MEK1/2 inhibitor U0126 causes enhanced cell killing in vitro. Cancer Biol Ther 2003; 2(6):670-676.

11. Wiesenauer CA, Yip-Schneider MT et al. Multiple anticancer effects of blocking MEK-ERK signaling in hepatocellular carcinoma. J Am Coll Surg 2004; 198(3):410-421.

12. Morgan MA, Dolp O et al. Cell-cycle-dependent activation of mitogen-activated protein kinase kinase (MEK-1/2) in myeloid leukemia cell lines and induction of growth inhibition and apoptosis by inhibitors of RAS signaling. Blood 2001; 97(6):1823-1834.

13. Favata MF, Horiuchi KY et al. Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem 1998; 273(29):18623-18632.