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-HT1B, AT1 and ETB 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
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Friday BB and Adjei AA. Advances in Targeting the Ras/Raf/MEK/Erk
Mitogen-Activated Protein Kinase Cascade with MEK Inhibitors for Cancer
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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.