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INTRODUCTION Out of the three different splice variants of RAF, mutations within the B-Raf oncogene result into a missense mutation within the BRAF kinase. This mutation is commonly seen in many kinds of cancers. The cancer cells harboring this mutation become resistant to various chemotherapeutic agents. Hence an inhibition which can target the substitution of val with glutamic acid at the 600th position will be therapeutically very important. Several inhibitors have been designed which show a potent action against Raf. After high throughput screening of this library of Raf inhibitors scientists found out the novel molecule PLX4720 which was highly efficient in inhibiting BRAF V600E. SEARCH FOR B-RAF KINASE INHIBITOR WITH ANTI-MELANOMA ACTIVITY Raf inhibitors which were previously discovered failed due to two primary reasons one being the lower bioavailability and another one being non specific action of these inhibitors. The most recent technique involved in the process of drug discovery is based on the scaffold structure investigation. This approach helps in the identification of specific inhibitors of phosphodiesterases. This structure activity based approach led to the discovery of PLX4720. This new molecule is derived from 7-azaindole and inhibits the B-RafV600E mutation at a concentration of 13 nM. It showed selective action in various biochemical assays. It showed cytotoxic effects only within those cells which had this mutation. It arrested the cell cycle and stimulated apoptosis within those cells showing this mutation. It delays the tumor growth and does not stimulate toxic effects within normal cells [1]. EFFECT OF PLX4720 ON ERK SIGNALING Mutations within BRAF or the Ras ultimately affect the signaling which is dependent on ERK. Vital biological processes like proliferation and growth are controlled by the effector molecule-ERK. Hence when these mutations stimulate the up-regulation of the ERK pathway these processes are hastened and selective inhibitors to these kinases like PLX4720 control the rate of proliferation efficiently. Few other tumor cells which contain an EGF receptor act via MEK (acts as an effector molecule). PLX4032 is not effective in case of those tumors which show a malfunctioned HER kinase. MEK specific inhibitors are active against Ras dependent mutations and PLX4032 is functionless within these cells. Hence PLX4032 is not an EGFR inhibitor and it is sensitive in only those cells which show BRAFV600E mutation. Within the WT-BRAF cells it activates the phosphorylation of ERK and MEK. Due to this selective action this inhibitor has gained therapeutic significance [2]. PLX4720 OVERCOMES THE RESISTANCE BY PIK3CA THROUGH TRAIL Colon cancer cell usually show a large variation and complexity in mutations. The oncogenic mutations within BRAF or KRAS are accompanied with mutated PI3K or PIK3CA. As a result of this the MEK inhibitors fail to act successfully. The BRAF inhibitor PLX4720 also failed to show efficient results. Two different cell lines of colon cancer we taken and subjected to the combination of (PLX4720+ TRAIL) and (17-AAG + TRAIL). The combination of (PLX4720+ TRAIL) sensitized the resistant cells to apoptosis. This provides a new strategy for anticancer treatment [3]. In case of cancers related to thyroid gland an operated removal of the thyroid gland along with the administration of PLX4720 extends the chances of survival [4]. CONCLUSION In summary PLX4720 shows a very specific action and inhibits the growth of only those tumors which show B-RafV600E mutation. Hence care should be taken while administering it under physiological conditions. 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. Josepha EW, Pratilas CA, et al. The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAFselective manner. PNAS 2010 Aug 17;107(33):14903–14908. 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. Nehs MA, Nagarkatti S, et al. Thyroidectomy with neoadjuvant PLX4720 extends survival and decreases tumor burden in an orthotopic mouse model of anaplastic thyroid cancer. Surgery 2010 Dec;148(6):1154-62; discussion 1162. Related Posts: TIPIFARNIB – INHIBITS FTP ENZYME SP600125 – A JNK INHIBITOR Related to PLX4720 – A SELECTIVE INHIBITOR WITH WIDESPREAD THERAPEUTIC APPLICATION PLX-4720 – STIMULATES APOPTOSIS WITHIN CANCER CELLS INTRODUCTION Large numbers of cancer cases are associated with modulations in the MAPK pathway. A larger percentage of these modulations within the MAPK pathway are ... PLX-4720 – EFFECTIVE IN CASE OF THYROID CANCERS INVOLVING MUTATIONS IN BRAF INTRODUCTION The gene which encodes for BRAF kinase plays a very important role in MAPK signaling pathway. The mutations within the BRAF gene stimulate the ... PLX-4720 – THE B-RAF INHIBITOR AGAINST MELANOMA INTRODUCTION: Since most of the cancers carry a mutation in Raf or Ras genes, targeting these mutations becomes a potent approach to inhibit aggressive cell ... We pays great attention to the purity, stability and activity of the products like Capecitabine, Lenalidomide, FTY720 & more. Not only could we provides the chemical test data, such as HNMR, LC-MS and HPLC, but also provides the reviews overall evaluations of the products from the customers who have used our products. Western Blot, MTT, RT-PCR, ICH photos or figures provide a double guarantee for the biological activities of our products in life-science research.
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