B-RAF INHIBITOR FOR TUMORS

by Selleckchem | Apr 23 2012

V600E MUTATION AND B-RAF PATHWAY:
B-Raf, a proto-oncogene is a serine/threonine kinase protein playing a major role in different signalling cascades which regulates cell growth and this B-Raf proto-oncogene in humans is encoded by B-RAF gene. B-Raf is found to be affecting the processes of cell division and cell differentiation by playing a regulatory role in ERK and MAPK signaling cascades. Any sort of acquired mutation in this gene leads to abnormalities in related signaling cascades as a result uncontrolled cell division and growth which leads to cancer eventually while an inherited mutation was found to be linked with cardiofaciocutaneous syndrome which is a birth defect. For this reason the use of B-Raf inhibitor for the inhibition of B-Raf pathways is found to be a valuable and attractive approach. More than thirty mutations found to be clustered in activation and flanking regions of B-Raf gene and they were analyzed as well. It was observed that substitution of Valine with Glutamic acid at codon number 600 is very abundant, clinically relevant and most famous one [1] and this mutation (V6000E) is targeted the most as compared to B-Raf selective inhibitor.

COMMONLY USED B-RAF INHIBITORS:
The purpose of developing the B-Raf inhibitor drug is to target those pathways in which mutations in which are related to various cancers [2] for example melanomas [3], leukemia [5], colorectal cancer [4] etc. Now more than one type of B-Raf kinase inhibitor is in market, some of which are Sorafenib tosylate, PLX-4720, GDC-0879 and PLX4032 etc. Each one of aforementioned examples of B-Raf antagonist has the potential to act as a single agent very effectively or also in combination with other inhibitors of some other pathways and provide good synergistic results. One can order B-Raf inhibitor for laboratory and research purposes from the company suppliers and the prices may vary from supplier to supplier. The most well known Raf inhibitor one is the PLX4032 and its clinical uses are given below.

B-RAF INHIBITOR: CLINICAL ASSESSMENT
As the relation between the cancer, B-Raf gene mutations and prolonged survival was verified, so a lot of number of B-Raf inhibitors were developed for use against cancers as a chemotherapeutic agents. PLX4032 is a BRaf inhibitor which is recently approved in clinical trials and is also known as Vemurafenib. The company that developed it is named as Plexxikon and the name of this inhibitor is originated from this drug manufacturing company which generates this molecule to work against tumors. FDA gave approval for the use of this drug to treat melanoma in 2011. A lot of clinical assays for the use of this drug against various types of tumors are in different stages of execution by the company Hoffmann–La Roche. V600E mutation carrying cancer cell lines, the PLX4032 has found to affect B-Raf/MEK/ERK cascade by inhibiting B-Raf/MEK. As it has been studied that almost 60% of melanomas are giving V600E mutation, So this inhibitor is very effective against them [6] while the cell lines having not this mutation don’t show any response to this drug. To determine its tolerability, maximum tolerated dose and safety; the clinical trials of phase 1 and 2 are going on in various cancer patients. The successful revelation of its pharmacodynamic and pharmacokinetic properties has prompted its use in different trials [7]. It has also generated very remarkable results in preclinical assays done in different in vivo and in vitro studies and cancer xenograft models.

REFERENCES:
1. Tan YH, e.a., Detection of BRAF V600E mutation by pyrosequencing. Pathology, 2008.
2. Davies H, e.a., Mutations of the BRAF gene in human cancer. Nature, 2002.
3. Maldonado JL, e.a., Determinants of BRAF mutations in primary melanomas. J. Natl. Cancer Inst, 2003.
4. Benlloch S, e.a., Detection of BRAF V600E mutation in colorectal cancer: comparison of automatic sequencing and real-time chemistry methodology. J Mol Diagn, 2006.
5. Tiacci E, e.a., BRAF mutations in hairy-cell leukemia. N. Engl. J. Med, 2011.
6. 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, 2010.
7. Flaherty KT, e.a., Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med., 2010.

Cat.No.	Product Name	Information
S1040	Sorafenib tosylate	Sorafenib tosylate is a multikinase inhibitor of Raf-1 and B-Raf with IC50 of 6 nM and 22 nM in cell-free assays, respectively. Sorafenib Tosylate inhibits VEGFR-2, VEGFR-3, PDGFR-β, Flt-3 and c-KIT with IC50 of 90 nM, 20 nM, 57 nM, 59 nM and 68 nM, respectively. Sorafenib Tosylate induces autophagy and apoptosis and activates ferroptosis with anti-tumor activity.
S1067	SB431542	SB431542 is a potent and selective inhibitor of ALK5 with IC50 of 94 nM in a cell-free assay, 100-fold more selective for ALK5 than p38 MAPK and other kinases.
S1152	PLX-4720	PLX4720 is a potent and selective inhibitor of B-Raf^V600E with IC50 of 13 nM in a cell-free assay, equally potent to c-Raf-1(Y340D and Y341D mutations), 10-fold selectivity for B-RafV600E than wild-type B-Raf.
S1104	GDC-0879	GDC-0879 (AR-00341677) is a novel, potent, and selective B-Raf inhibitor with IC50 of 0.13 nM in A375 and Colo205 cells with activity against c-Raf as well; no inhibition known to other protein kinases.