MEK INHIBITOR AGAINST UNCONTROLLED GROWTH OF CELLS

by Selleckchem | Aug 07 2012

MEK – RECEPTORS:
Growth factor receptor is found on the surface of cells and upon stimulation a protein is encoded in the nucleus which is vital for cell signaling. A type of kinases is called MEK that is important for the pro-survival signaling. An easy approach to hinder or control the pro-survival signaling is the inhibition of MEK which can be done by designing MEK kinase inhibitor. The most suitable example of is of cancer cells which is characterized by uncontrolled cell proliferation and in these cells MEK signaling pathway is found as hyperactivated, hence the introduction of MEK pathway inhibitors is the appropriate therapy. About 20 years back the structure of MEK was elucidated [1], due to this researcher are aided well for the development of specific MEK inhibitors.

PHARMACOLOGICAL PROPERTIES OF MEK INHIBITORS:
Development and designing of drugs for MEK inhibition includes many steps. Generally it includes small molecule library screening which are newly discovered. The next step is the verification and potency analysis of these molecules for selective MEK inhibition following the applications in in vivo and in vitro trials to analyze their efficiency in treating various diseases or dysregulation of MEK. Agonists or antagonists of MEK are also used for the understanding of MEK signaling pathway under specific conditions. In this regard an example is of PD98059 and U0126 assessment against osteoclastogenesis process of in vitro system, murine monocytic cell line named RAW264.7 and both of these chemicals enhanced the differentiation of these cell lines into osteoclast like cells [2]. MEK inhibitors have normal price and researchers are confident about using these inhibitors. Two most common MEK inhibitors used for research studies are PD98059 and U0126 due to their specific action. MEK suppliers are there for the selling of MEK inhibitors and one can easily buy these chemicals.

MEK INHIBITORS AND CLINICAL TRIALS:
In a research work it is reported that various molecules containing cyanoquinoline are proved as potent inhibitors of MEK which are able to check the growth of tumors. Alkoxy group substitution at 6- and 7-positions highlighted the potency of these compounds for MEK inhibition [3]. U0126 and Paclitaxel when used in the combination the growth and proliferation of tumor cells was suppressed and also a synergistic effect reported in the form of apoptosis when both of these inhibitors were applied simultaneously [4]. Many years back U0126 was found to be active inhibitor of MEK and specific as well and this was also reported that this inhibitor works as an antagonist of AP-1 by targeting its transcriptional actions caused by checking of MEK signaling pathway non-competitively [5]. PD98059 and PD184352 are two small molecules which were called for the clinical trials after their discovery and these were assessed for acute myeloid leukemia or impaired cellular growth. These inhibitors were found to be active in targeting the growth of leukemic cells leaving normal progenitor hematopoietic cells [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.