MEK PATHWAY INHIBITION FOR CANCER THERAPY

by Selleckchem | Aug 13 2012

SIGNALLING OF MEK PATHWAY:
Various types of cells exist on the surface of the cells helping the cells to coordinate with the environment and the other cells. The growth factor receptors are such receptors which after getting triggered by the ligands usually play a very vital role in the process of cell signaling hence stimulate different pathways that are necessary for the cell survival and growth. One such example is MEK kinase cascade that plays an important role in pro-survival signaling. The inhibition of MEK kinase pathway is one of the attractive strategies when there is a need to inhibit un-necessary proliferation of cells in case of cancer. It has been studied that MEK signaling pathway gets hyperactivated in the cancer cells, so scientists devised a good therapeutic tool against cancer by designing different inhibitors of MEK pathway. 20 years ago, the structural properties of MEK molecule were described [1], which make the approach of scientists much easier for specific MAP2k2 inhibitor.

MEK INHIBITORS: PHARMACOLOGICAL PROPERTIES:
Search for designing drugs or inhibitors is a multistep procedure starting from construction to molecule library and its confirmatory tests for its potency and then its applications in vivo and in vitro clinical trials to check its efficacy in treating various diseases exhibiting the dysregulated form of MEK pathway. The small molecules using as the antagonists and agonists are helpful to understand MEK and its signaling cascade in various conditions. PD98059 and U0126 are the famous examples of such smaller molecules that are in use to access the osteoclastogenesis in in vitro system i.e., RAW264.7 that are murine monocytic cells. These molecules increased the differentiation of cell lines into the osteoclasts resembling cells [2]. These are the most commonly used MEK inhibitors due to their specific reactivity. These inhibitors are easily and commercially available in market at very reasonable prices and the researchers can buy them from the MEK suppliers and use them for different purposes.

MEK INHIBITORS: CLINICAL TRIAL
Now it has been revealed that there are many molecules that have been designed and have the capability to inhibit the MEK pathway hence preventing the growth of tumor or cancer. It is observed that the structure of these molecules contain cyanoquinoline. At 6- and 7 position the substitution of alkoxy group indicates their potency of MEK inhibition [3]. U0126 and Paclitaxel, irrespective of their single use, when combined, showed a synergistic effect by suppression of growth and proliferation of cancer cells hence causing apoptosis [4]. A long time ago U0126 was seen to specifically and actively inhibit MEK pathway and was also observed to play its role as an AP-1 antagonist by checking signal of MEK non-competitively and as a result inhibition of its transcriptional activation occurs [5]. Other two molecules are PD98059 and PD184352 were brought to the clinical trials after their discovery. They were assessed against acute myeloid leukemia or AML and their role was tested against the impaired growth of cells. Both of them were seen to inhibit growth in leukemia cells and leaving the normal hematopoietic progenitor cells as unaffected [6].

REFERENCES:
1. Crews CM, e.a., The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product. Science, 1992.
2. Hotokezaka H, e.a., U0126 and PD98059, Specific Inhibitors of MEK, Accelerate Differentiation of RAW264.7 Cells into Osteoclast-like Cells. JBC, 2002.
3. Zhang N, e.a., Synthesis and Structure-Activity Relationships of 3-Cyano-4-(phenoxyanilino)quinolines as MEK (MAPKK) Inhibitors. Bioorganic & Medicinal Chemistry Letters, 2000.
4. MacKeigan JP, e.a., MEK Inhibition Enhances Paclitaxel-induced Tumor Apoptosis. JBC, 2000.
5. Duncia JV, e.a., MEK inhibitors: The chemistry and biological activity of U0126, its analogs, and cyclization products. Bioorganic & Medicinal Chemistry Letters, 1998.
6. Milella M, e.a., Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia. J Clin Invest., 2001.

Cat.No.	Product Name	Information
S1177	PD98059	PD98059 is a non-ATP competitive MEK inhibitor with IC50 of 2 μM in a cell-free assay, specifically inhibits MEK-1-mediated activation of MAPK; does not directly inhibit ERK1 or ERK2. PD98059 is a ligand for the aryl hydrocarbon receptor (AHR) and functions as an AHR antagonist.
S1102	U0126-EtOH	U0126-EtOH is a highly selective inhibitor of MEK1/2 with IC50 of 0.07 μM/0.06 μM in cell-free assays, 100-fold higher affinity for ΔN3-S218E/S222D MEK than PD98059. U0126 inhibits autophagy and mitophagy with antiviral activity.
S1020	PD184352 (CI-1040)	PD184352 (CI-1040) is an ATP non-competitive MEK1/2 inhibitor with IC50 of 17 nM in cell-based assays, 100-fold more selective for MEK1/2 than MEK5. PD184352 (CI-1040) selectively induces apoptosis.
S1150	Paclitaxel	Paclitaxel is a microtubule polymer stabilizer with IC50 of 0.1 pM in human endothelial cells.Paclitaxel can cause both mitotic arrest and apoptotic cell death. Paclitaxel also induces autophagy.