CI-1040 – A Powerful and Selective MAPK Inhibitor

INTRODUCTION:

CI-1040 is a mitogen-activated inhibitor, which can be given orally, and which can regulate MEK via extracellular signal. MEK is one of the key enzymes which belong to the Ras-Raf-MEK-extracellular signal kinase (ERK). This enzyme is famous as a key player in the cellular activities, like differentiation, proliferation, angiogenesis and apoptosis [1-5]. Since this pathway performs activities in various solid tumors, like cancers in colon, breast and pancreas, etc [6-7]. Therefore, CI-1040 could be a key molecule in the prevention and retardation of various solid tumors inside the body

CI-1040 – A POWERFUL AND SELECTIVE INHIBITOR:

CI-1040 has been considered as a first MEK targeted molecule in various clinical studies. This molecule is found highly powerful and selective inhibitor for both types of MEK 1 and MEK 2. The amount required to inhibit MEK1 (IC50), is very little, i.e. 17 nmol/L [8 and 9]. The molecule exhibits non competitive nature with adenosine triphosphate

MECHANISMS AND ACTIONS:

CI-1040 is exclusively selective for MEK, as it cannot inhibit the panel of kinases at the concentration of 10 M. a hydrophobic binding pocket was found adjacent and somehow distant to the magnesium ATP binding site [10], in the three dimensional structure of MEK1 and 2, which are bound to Mg-ATP and CI-1040 like molecule. When CI-1040 binds with this unique site, a conformational change takes place in unphosphorylated MEK which makes it locked closely, and in inactive form. This whole mechanism of MEK inhibition shows the high degree of enzyme specificity seen for CI-1040 and its related other compounds.

RESEARCH STUDIES:

There are various research studies which show that CI-1040 can inhibit the clonogenic growth of various solid tumor cell lines. The cancers which can be inhibited by this molecule may be from a dissimilar origin, having constitutive phosphorylated ERK levels (more sensitive) [9]. Along with the antiproliferative properties, CI-1040 can cause a dose-dependent G1 block. This shows that how much CI-1040 is effective in inhibiting the MAPK pathway, since for activation this pathway requires to pass from G1 restriction point [11].

During research studies, it has been found that CI-1040 shows important antitumor activities both in human beings and the rats. These tests were done on different types of solid tumors like breast, colon, pancreas, lungs and kidneys [12]. According to the research studies, the tumors that have been excision after employing the CI-1040 have shown complete suppression of ERK phosphorylation up to six hours, and their control levels have been obtained up to 24 hours after a single oral dose of bcl-2 inhibitors [9]. These experiments show that CI-1040 should be given on a daily basis in order to keep the MAPK phosphorylation suppressed and ineffective.

CONCLUSION:

In summary, the targeting of tumor cells by means of inhibiting the Ras-Raf-MEK-ERK pathway is effective one and it could be attained by means of a wonderful molecule known as CI-1040. This molecule possesses extremely superior and biochemical properties and it can suppress the MEK pathway with up to 50 folds greater potency. This molecule should be used as an initial one or in the secondary regimes in order to address the tumor growths all over the human body.

REFERENCES:

1. Cowley S, Paterson H, Kemp P, et al: Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell 77:841-852, 1994.

2. Mansour S, Matten W, Hermann A, et al: Transformation of mammalian cells by constitutively active MAP kinase kinase. Science 265: 966-969, 1994.

3. Pang L, Sawada T, Decker SJ, et al: Inhibition of MAP kinase kinase blocks the differentiation of PC-12 cells induced by nerve growth factor. J Biol Chem 270:13585-13588, 1995.

4. Holmstrom TH, Tran SE, Johnson VL, et al: Inhibition of mitogen-activated kinase signaling sensitizes HeLa cells to Fas receptormediated apoptosis. Mol Cell Biol 19:5991-6002, 1999.

5. Elliceiri B, Klemke R, Stromblad S, et al: Integrin alphavbeta3 requirement of sustained mitogen-activated protein kinase activity during angiogenesis. J Cell Biol 140:1255-1263, 1998.

6. Sebolt-Leopold J, VanBecelaere K, Dudley D, et al: Blockade of the MAP kinase pathway retards growth of murine and human tumors in vivo. Proc Am Assoc Cancer Res 40:118, 1999 (abstr).

7. Hoshino R, Chatani Y, Yamori T, et al:Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene 18:813-822, 1999.

8. Sebolt-Leopold J, Van Becelaere K, Dudley D, et al: Blockade of the MAP kinase pathway retards growth of murine and human tumors in vivo. Proc Am Assoc Cancer Res 40:40, 1999 (abstr 785).

9. Sebolt-Leopold JS, Dudley DT, Herrera R, et al: Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat Med 5:810-816, 1999.

10. Ohren J, Chen H, Pavlovsky A, et al: Structures of human MAP kinase kinase 1 (MEK 1) and MEK2 describe novel noncompetitive kinase inhibition. Nat Struct Mol Biol 11: 1192-1197, 2004.

11. Pages G, Lenormand P, L'Allemain G, et al: Mitogen-activated protein kinases p42-mapk and p44-mapk are required for fibroblast proliferation. Proc Natl Acad Sci U S A 90:8319-8323, 1993.

12. Allen LF, Sebolt-Leopold JS, Meyer MB: CI-1040 (PD-184,352), a targeted signal transduction inhibitor of MEK (MAPKK). Semin Oncol 30:105-116, 2003.

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