subject: An Introducton Of Plx-4720 [print this page] The region within the PLX4720 which binds to B-Raf protein, which is mutated at the 600th position (valine is replaced by glutamic acid) has a scaffold region which typically overlaps the adenine attaching site. However the tail of PLX4720 does not bind to the region which is meant for the binding of ribose-triphosphate terminus of ATP. PLX4720 binds to the selective site within the B-Raf, which is present in its active conformation. It binds to the general pocket of the kinase enzyme when it exists in the inactive conformation [1].
PLX4720 EFFECT ON BRAFV600E MUTATION
This mutation in the BRAF gene is the most common mutation which leads to different kinds of cancers. Those inhibitors which target the active form of this protein kinase are used to higher extent for therapeutic purposes. The inhibitor PLX4720 targets V600E allele more precisely and acts against the active form of the kinase enzyme. It is a derivative of 7-azaindole and inhibits this mutant form of BRAF at a concentration of 13 nM. This inhibitor is selectively toxic to those cells which contain V600E allele and reduces the levels of phosphorylation of ERK within these cells. It arrests the cell cycle and stimulates the process of apoptosis within these cells [1].
PLX4720: SHOWS AN EXCELLENT ANTI-MIGRATORY ACTIVITY
Mutation on the BRAF gene at the 600th position is very essential for the advancement of PTC (papillary thyroid cancer). PLX4720 was tested within human cell lines and was found to be a potent inhibitor of the process of proliferation and migration of cancer. It down regulates the genes which are responsible for the progression of tumor. However the cell invasion was not blocked in case of TPC-1 cells by PLX4720. This inhibitor also tries to upregulate the process of differentiation and inhibits the aggressiveness of tumor within the thyroid gland [2].
PLX4720: REQUIRES THE ASSISTANCE OF TRAIL
Inhibition of the process of cell proliferation in case of colon cancer cells is difficult as they show co-existence BRAFV600E mutations along with those in PIK3CA and PI3K. This does not allow the MEK inhibitors to act successfully. In some cases the cells became totally resistant to cell death after the application of PLX4720. However when PLX4720 was administered along with TRAIL, the suppression of PI3K pathway was observed. This combination stimulated the process of apoptosis [3].
PLX4720: ACTION ON MEK RESISTANCE
Most of the cancers are related to the mutations in the BRAF gene and they increase the sensitivity to the MEK inhibitors. Mutations which offer resistance to MEK inhibitors promote the formation of an allosteric drug attaching pocket. This stimulates the resistance to the MEK1/2 at the allosteric sites. Administration of PLX4720 does not allow the resistant clones to develop hence suggesting that it has vital clinical applications.
CONCLUSION
In a nut shell PLX4720 is very specific to those cancers which show mutation in the 600th position within the BRAF kinase (replacement of valine with glutamic acid). It also overcomes the resistance offered to the MEK inhibitors.
REFERENCES
1. Tsai J, Lee JT, et al. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. PNAS 2008 Feb 26; 105(8); 3041-3046.
2. Nuceraa C, Nehsa MA, at al. Targeting BRAFV600E with PLX4720 Displays Potent Antimigratory and Anti-invasive Activity in Preclinical Models of Human Thyroid Cancer. The Oncologist 2011 March; 16(3); 296-309.
3. Oikonomou E, Koc M, et al. Selective BRAFV600E Inhibitor PLX4720, Requires TRAIL Assistance to Overcome Oncogenic PIK3CA Resistance. PLoS ONE 2011; 6(6).
4. Emery CM,KrishnaG. MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc Natl Acad Sci U S A 2009 Dec 1; 106(48): 2041120416.
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