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IMPLICATIONS OF B-RAF OVER-ACTIVATION: B-Raf pathway is implicated in cellular processes like cell growth, survival and sustained proliferation of the cells. The Raf/MEK/ERK pathway has been known to be contributing to the aforementioned signaling cascades [1]. Since the over-activation of these protein kinases is reported to be involved in many molecular pathways causing cells to turn cancerous, the down-regulation of these signaling cascades using B-Raf pathway inhibitors seems to be a promising approach in developing a therapeutic regime for treating cancers. Also, mutations in B-Raf genes are linked with enhanced tumorigenesis of many cancers [2] and hence targeting the cancer cells harboring these mutations to achieve B-Raf inhibition with the help of any of the various B-Raf inhibitors is becoming increasingly tried approach. Out of almost 30 known mutations in B-Raf gene, the mutation at 600th codon replacing a valine with a glutamate or more commonly known as V600E mutation is linked with many kinds of melanoma, thyroid cancer [3], colorectal cancer and leukemia [4] etc. hence many B-Raf inhibitors drugs are designed specially around this molecule. PHARMACOLOGICAL PROPERTIES OF B-RAF INHIBITORS: The most well known B-Raf kinase inhibitors are Sorafenib and Vemurafenib apart from other inhibitors like GDC-0879 and PLX-4720 which are being developed by various pharmaceutical companies. All these B-Raf antagonists can differ from each other in terms of their specificity towards B-Raf inhibition, towards V600E mutations and in terms of their ability to affect any other kinase too. For example, whereas Vemurafenib is very potent against cells harboring V600E mutation, having opposite effects on non-V600E mutation carrying cells [5]; Sorafenib is a multiple kinase inhibitor which affects VEGF-R, PDGF-R and C-Raf signaling equally [6]. All these molecules are available easily and one can buy B-Raf inhibitors for laboratory and research purposes. B-RAF INHIBITORS AT CLINICAL LEVEL: Vemurafenib is developed by the drug manufacturing company Plexxikon and hence is also known as PLX4032. This molecule is one the most potent B-Raf selective inhibitors and after the remarkable results generated in the clinical trials conducted by Hoffmann–La Roche, Vemurafenib very recently received FDA approval for its use in the treatment of late-stage melanoma [7]. There are more examples of B-Raf inhibitors in clinical trials and Sorafenib is one of them which can effectively target cells that do not harbor a V600E mutation in B-Raf [8]. As stated above, rather than being a specific Raf inhibitor, it targets other receptor as well as intracellular kinases too. Sorafenib also got FDA approval for its use in treatment of patients suffering from advanced renal cancer (RC) after it was seen to be very successful in various in vitro and in vivo models of RC. In hepatocellular carcinoma (HCC) patients also, Sorafenib showed good efficiency [9] and is on its way to be an approved part of their treatment regime. Also known as BAY 43-9006, Sorafenib is dual-action inhibitor that targets Raf kinases and VEGF-R inhibition effectively in phase I studies on advanced and refractory form of solid tumors [10]. PLX4720 is another example of B-Raf specific inhibitors [11]. REFERENCES: 1. Wan PT, e.a., Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-Raf. Cell, 2004. 2. Davies H, e.a., Mutations of the BRAF gene in human cancer. Nature, 2002. 3. Saenko VA, e.a., Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. J. Clin. Endocrinol. Metab., 2003. 4. Tiacci E, e.a., BRAF mutations in hairy-cell leukemia. N. Engl. J. Med, 2011. 5. Hatzivassiliou G, e.a., RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature, 2010. 6. Wilhelm SM, e.a., Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Molecular Cancer Therapeutics, 2008. 7. Halaban R, e.a., PLX4032, a Selective BRAF(V600E) Kinase Inhibitor, Activates the ERK Pathway and Enhances Cell Migration and Proliferation of BRAF(WT) Melanoma Cells. Pigment Cell Melanoma Res, 2010. 8. Smalley KSM, e.a., CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations. Oncogene, 2009. 9. Keating GM, S.A., Sorafenib: A Review of its Use in Advanced Hepatocellular Carcinoma. Drugs, 2009. 10. Strumberg D, e.a., Phase I Clinical and Pharmacokinetic Study of the Novel Raf Kinase and Vascular Endothelial Growth Factor Receptor Inhibitor BAY 43-9006 in Patients With Advanced Refractory Solid Tumors Journal of Clinical Oncology, 2005. 11. Tsai J, e.a., Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. PNAS, 2008 As one of the world leading suppliers of high-performance life-science products. We have over 8,000 products which consist of inhibitors, antibodies, RNAis, proteins and peptides those which focus on signaling pathways such as Gefitinib, Erlotinib, Lapatinib, Imatinib, Rapamycin & so on. Furthermore, compound libraries for high-throughput screening and high-content screening are also available.
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