THE ROLE OF THE MAPK PATHWAY UNDERSTOOD WELL WITH THE HELP OF SB590885

The disease cancer is associated with a number of modifications and alterations in various signaling pathways. Amongst the various intracellular pathways, MAPK pathway has been found to be commonly hyper-activated in many cases of cancers. The normal functioning of the MAPK pathway is required for many vital functions like proliferation of the cell, regulation of the cell cycle, migration of the cell from one point to another and development of new blood vessels from the older ones. This pathway sends the extracellular signals to the nucleus. The components of this pathway are involved in a cross talk with many other members who belong to other pathways. The hyper-activation of this pathway can be controlled with the help of certain inhibitors which can control the overstimulation of the kinases. SB590885 is one such inhibitor.

SB590885 INHIBITS THE ACTIVITY OF BRAF

The MAPK pathway originates from Ras, which sends the signal for the activation of different splice variants of RAF.  The three different splice variants of Raf are Raf-1, A-Raf and B-Raf. These splice variants bind to the ras and as a result, the complex is recruited to the membrane. This involves the phosphorylation of many co factors. The signal from Raf gets transmitted down through MEK1/2 and ERK1/2. Specific inhibitors are being designed which can target different components of the pathway. Inhibitors which target MEK were U0126 and PD 098059. Amongst these U0126 blocked the AP-1 mediated transcription. CI-1040 is another inhibitor which has received clinical approval and it makes the heterotransplants sensitive to paclitaxel [1]. Similarly an inhibitor which inhibits the upstream kinase that is B-Raf kinase is SB-590885. It is derived from triarylimidazole and it is highly selective in its action [2]. The antitumor activity of docetaxel was further enhanced by MEK inhibitor AZD6244.

SB590885 HELPS IN THE STUDY OF CEREBROVASCULAR CONTRACTILE RECEPTORS

The cerebrovascular receptors such as 5-HT_1B, AT₁ and ET_B were found to be significantly increased within the vessel walls of the ischemic region. The increased expression of these receptors enhances the damage to the tissues by impairing the blood flow. These receptors get activated through the MAPK pathway. SB-386023 helped in the study of these receptors as it specifically inhibits B-Raf. When the Braf kinase was inhibited the expression of the contractile receptors was hampered. Hence the tissue damage can be prevented by inhibiting the Raf kinase activity [3].

SELECTIVE ACTION OF SB590885 ON BRAF ^V600E

The solid tumors are generally enhanced through signaling factors which are stimulated by the growth factors. Some MEK inhibitors which act as MAPK inhibitors show a synergistic action with EGFR inhibitors. Mutations within the BRAF kinase are commonly associated with many kinds of cancers especially in case of melanomas. SB-590885 helped in the analysis of the role of MAPK pathway, especially B-Raf kinase for the growth of tumor. Colorectal cancers and melanomas are usually associated with mutation BRAF ^V600E; hence these cells lines were tested with SB590885. The concentration of SB-590885 which was just sufficient to inhibit ERK was enough to curtail the growth and proliferation of the tumor cells. This shows that mutation within BRAF plays a primary role in stimulating colorectal cancers and melanomas [4].

CONCLUSION

In a nut shell SB-590885 checks the growth of those cancers which contain mutated BRAF kinase. It has helped the scientists to study the role of MAPK within various cancers.

REFERENCES

1. Friday BB and Adjei AA. Advances in Targeting the Ras/Raf/MEK/Erk Mitogen-Activated Protein Kinase Cascade with MEK Inhibitors for Cancer Therapy. Clin Cancer Res 2008 Jan 15; 14; 342.

2. Taklea AK, Brown MJB, et al. The identification of potent and selective imidazole-based inhibitors of B-Raf kinase. Bioorganic & Medicinal Chemistry Letters 2006 Jan 15; 16(2); 378-381.

3. Ahnstedt H, Säveland H, et al. Human cerebrovascular contractile receptors are upregulated via a B-Raf/MEK/ERK-sensitive signaling pathway. BMC Neurosci 2011 Jan 11; 12:5.

4. King AJ, Patrick DR, et al. A novel, potent and selective small molecule inhibitor of B-Raf kinase, SB-590885, inhibits signal transduction and growth of cells bearing the B-Raf V600E mutation. Proc Amer Assoc Cancer Res 2005; 46.