Ise k is some concern about the clinical safety of PLX4032, the high expression and uncontrollable lead Nnte Lee MEK1 / 2 and ERK1 / 2 in melanoma RAS and N and normal cells mutate, thereby acquiring them BMS-354825 cancer properties leads to other cancers. RAF V600EB inhibited in tumors, RAS is not enabled, the minimum trans-activation and ERK in the cells exposed to RAF inhibitors. RAF inhibitors such as 4032 may be effective in tumors PLX in which B RAF is mutated, as it does not inhibit ERK signaling in normal cells. Therefore, PLX4032 has a therapeutic index gr He and gr He Antitumoraktivit t MEK inhibitors, which are soup ONED to toxicity T by MEK / ERK activation in normal cells cause. K mutant RAS and RAS / RAF wild-type tumors RAF inhibitors are known, the MAP kinase pathway in a RAS-dependent turn-dependent, A erh FITTINGS tumor growth in xenograft models some what.
Binding inhibitor KW-2478 active isoforms of wild-type RAF induction by dimerization, membrane localization and interaction with GTP RAS. These events occur independently Ngig of kinase inhibition and are the direct impact of the conformation of the kinase Dom related ne RAF inhibitors. XL281 is a potent and specific inhibitor of the other three RAF kinases. W During genotyping and selection of patients is necessary prior to treatment with PLX4032 not XL281 not required, the selection of patients. A Phase I study recently tested the effectiveness of XL281 in seven cancer of the thyroid gland Than five years and five melanoma patients. The results were disappointed Uschend because the drug induced epidermal carcinoma Registered and the Born systemic toxicity t.
Although progress in the development of drugs, the RAF, the clinical results for long-term use, mechanism of action, specificity t, Therapeutic efficacy and toxicity of t Drug-targeting needs made further evaluation. In addition to the development of inhibitors of the RAF, it is also important, the results of recent studies show that B-RAF inhibition could f to tumor development in cells Rdern to consider that harbor RAS mutations. RAF inhibitors mightactivate the MAPK signaling cascade and f Rdern the growth of tumors harboring mutant RAS and K RAS wild type. A recent study showed that inhibition of RAF V600EB for melanoma development delay Delay k Nnte to the development of metastatic melanoma L Emissions at an early stage one, which requires combinatorial Ans PageSever to treat this disease.
In this study V600EB RAF has been shown, the marker protein microtubule-associated neuronal differentiation in melanoma cells by triggering sen Activate promoter demethylation and the down-regulation of transcriptional HES1. Ectopic expression of MAP2, an important indicator of tumor progression, inhibited cell cycle caused M Deficiencies in the mitotic spindle, which resulted in growth inhibition and apoptosis. 2.6. To inhibit melanoma are targeting MEK MEK 1 and MEK 2 dual specificity Tyrosine / threonine protein kinases t found that active in 30% of all human cancers with activated MAPK. These proteins Behind RAF and B shares 80% structural homology. ERK is the only known substrate of MEK 1 and 2 MEK kinases. Therefore continue to MEK 1/2 to popular therapeutic targets in the MAPK cascade to be. Several studies