Friday, March 23, 2012

SB590885 – HELPS IN THE EXPLORATION OF THE ROLE OF B-RAF MUTATION


INTRODUCTION

Detection of the exact cause behind cancer is a breakthrough achievement as cancers show large scale heterogeneity. Alterations in different pathways lead to different kinds of cancers. In order to identify the correct genotype of the tumor, it is very essential to identify the genes which get mutated or amplified. Mutated KRAS and BRAF genes are most commonly noticed in case of neoplasm and pancreatic cancer. The primary condition necessary for the development of tumor is considered to be activation of the BRAF gene. SB590885 targets this mutation.

SB590885 HELPS IN THE STUDY OF ONCOGENIC BRAF

Among the various mutations which affect the regulatory domain of B-Raf, the exchange of amino acids at the 600th position (Val with Glu) is very important. This mutation creates a bypass pathway for the activation of kinases. The cells no longer require the stimulus of growth factors and moreover kinases are activated at least 500 times in this case. When this mutation was suppressed by knock down the survival of the tumor cells was altered. The significance of the mutation within the Braf gene was further explored, by the use of SB590885 which inhibits the kinase activity. SB590885 inhibited the growth of tumors and research using this inhibitor showed that cancer causing mutations within the Braf gene can be vital therapeutic targets. In many cases of cancers the amplification of the pathways which involve growth factors is also noticed. This led to the development of inhibitors like erlotinib, lapatinib and gefitinib. These inhibitors targeted the receptors of the growth factors belonging to the Erb family. There is a strong correlation between the presence of an oncogene and positive effect of an inhibitor. Hence obtaining the genetic signature in case of different tumors can help in the development of targeted therapy [1].

STRUCTURE AND MECHANISM OF ACTION OF SB590885

SB590885 is relatively newly discovered inhibitor of kinase which has been derived from triarylimidazole basic structure. It contains an oxime substituent. It shows selective and efficient inhibition of B-Raf kinase [2]. Inhibitors which specifically target the growth receptors belonging to Erb family have shown a strong correlation between the signaling pathways and the cancer phenotypes. The necessity of the growth factor for the normal functioning of the cell can be replaced by few mutations within the downstream effectors. The relationship between the MAPK signaling and the growth of tumor was identified with the help of SB-590885. Various colorectal cancer cell lines and melanoma cells were tested under in vitro conditions for survival and growth after the administration of SB-590885. The choice of the cancer cell lines was made on the basis of the presence of B-Raf V600E mutation. SB-590885 exhibited a cytotoxic and cytostatic method of inhibition of growth [3]. The MAPK pathway gets stimulated by the activating mutations within BRAF. It is a vital component and seen in case of many thyroid cancers. SB-590885 checks the proliferation and stimulates the process of apoptosis within cancerous cells [4].

CONCLUSION

In summary SB-590885 has helped to study the role of BRAF mutations within the development of cancers. It surpasses the action of egfr inhibitors.

REFERENCES

1. King AJ, Patrick DR, et al.  Demonstration of a Genetic Therapeutic Index for Tumors Expressing Oncogenic BRAF by the Kinase Inhibitor SB-590885. Cancer Res 2006 Dec 1; 66: 11100.
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. 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. AACR Meeting Abstracts 2005; Abstract No: 5286: 1250-a.
4. McCubrey JA, Steelman LS, et al. Emerging Raf inhibitors. Expert Opin Emerg Drugs 2009 Dec; 14(4):633-48.

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