In normal functioning of cells MAP kinase pathway plays a crucial role. When any factor changes this pathway to a hyperactive form, pathways like cellular growth, proliferation, survival and apoptosis are disturbed and it leads to the formation of tumor or cancer.  Mitogen activated protein kinase (MAPK) signaling pathway has been thoroughly studied and molecules which can inhibt this vital pathway at various stages are designed by high throughput screening. One the potent kinase inhibitor is RAF265 which strongly checks the MAP kinase pathway.

Raf kinase is one of the most initial kinase, the mutations of this kinase lead to the hyperactivation of some other kinase enzymes present to downstream. These downstream kinases include ERK which is activated vis MEK1/2.  This mutation of Raf is associated with vast variety of cancers. Ras kinase family is linked with GTPase which influences the MAP kinase components. The mutations in the Ras kinases are also linked with different cancer formations. Upon hyperactivaiton of ERK the expression of EGFR is enhanced.  The effects of RAF265 were studied which blocked these mutated forms of kinases. This inhibitor was also very useful for the understandings of MAP kinase pathway for the cancer research.

In addition to the Raf gene the Ras kinase mutations also result in the formation of various cancers. This mutated gene is difficult to handle for the treatment of cancer. Various alternative ways are used to inhibit the MAP kinase pathway by discovering new inhibitors via screening of MAP kinase inhibitor compound library. One of these alternative approaches is to aim the downstream components of the MAP kinase pathway. During preclinical studies of certain inhibitors of downstream components like RAK or MEK it was shown that the BRAF or Ras mutated kinases creates resistance against these inhibitors. Specifically mutations at 600th position of BRAF genes, and 265th position of Raf kinase genes offered resistance. The rate of apoptosis was enhanced when the D3 protein kinase was knocked out. These results suggested the role of PRKD3 suppression affects the inhibitors of RAK and MEK by stimulating them with the help of RAF265. This leads to the tumor suppression by apoptosis. PRKD3 inhibition and the actions of RAF265 combine to target the tumor cells and the growth and proliferation of the cells ceases.

Many of the anti-cancer agents and inhibitors fail to inhibit the actions of hyperstimulated KRAS or PI3K ¨CAKT because these genes are resistant to EGFR inhibitors. These over-activated pathways were inhibited by the actions of RAF265.  The studies under in vivo and in vitro conditions was carried out when RAF265 was used in combination with RAD001, dual effect of these agents strongly inhibited the tumor growth. Mutated BRAF kinases were also inhibited by this novel compound as it targeted the Raf downstream components. RAD001 efficiently blocked the enzymes present at downstream to mTOR. When HCT116 cell lines were tested against this combination the ruction in AKT, S6 and eIF-4E binding protein-1 phosphorylation was observed. Both inhibitors reinforced the effects of each other. Hence the inhibitors to mTOR and RAF265 together inhibit the vital components of MAP kinase pathway which ultimately leads to the cancerous cells death. In another study it was noticed that the TRAIL ligand sensitivity was enhanced when RAF265 was used.

CONCLUSION

In a nut shell, RAF265 efficiently inhibits the mutated forms of various MAP kinases including RAF kinase. This compound also works well in the presence of other inhibitors. Blockage of MAP kinase pathway by the RAF265 leads to the tumor suppression or cancerous cell apoptosis.



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