Ted tested the growth inhibitory effects of kinase inhibitor sorafenib in eight different multiple cultures metastatic melanoma cell lines. Moreover k Nnten Combined with sorafenib Lonafarnib induce apoptosis and to abolish the invasive potential of melanoma cells. Besides RTI have developed pharmacological CYT997 agents directly to the RAS and also inhibit evlauated in pr Clinical trials and in clinical studies of melanoma. BMS 214,662 and 778,123 L, non-peptidic inhibitors of RAS H and K were each tested against melanoma. In a phase I study in patients with solid tumors, the oral 214662 BMS experienced doselimiting toxicity t manifested by nausea, diarrhea, vomiting, Bauchkr Cramps, loss of appetite, fatigue and fever. Was 23 patients, with the exception of 1 disease.
Although the pharmacokinetics of the drug was favorable oral bioavailability in oral form proposed then abandoned because of gastrointestinal intolerance. In another phase I study was initially ITF2357 BMS 214662 Highest administered in 30 patients over a period of 1 hour per week. A minor response in a patient was refractory to chemotherapy Ren reported breast cancer. The 778,123 was also evaluated clinically by a continuous infusion for 5 days the agent alone or in combination with radiotherapy and paclitaxel for the treatment of NSCLC, and carcinoma of the head and neck. Despite a good clinical response studies for lack of evidence relates to the heart sank, manifested as a Pub EXTENSIONS of the QTc interval. Unfortunately, these two compounds were ineffective in melanoma, like most port-RAS and N is not H or K-RAS mutations.
RAS inhibitor tested in combination with radiation or cytotoxic drugs in pr Clinical and clinical trials, and also ineffective. Thus, therapeutic targeting RAS in melanoma cells is relatively ineffective, suggesting that other points of the MAPK pathway may be the most promising targets. 2.3. Target for Melanoma B RAF RAF B is inhibiting one of three members of the RAF RAF family, the A, B and RAF CRAF lt contains, And is a downstream effector of RAS. The three isoforms of RAF S ugetieren While at the same three conserved regions are also significant differences in the variable sequences. CR1 contains Lt one Bindungsdom Ne and a cysteine-rich RAS Cathedral ne. The CR2 Cathedral ne Contains Lt serine and threonine residues, plays an r In regulating the activity B RAF t on phosphorylation.
CR3 contains Lt the kinase Dom ne and phosphorylation of key sites, the enzyme activity Regulate t. The activation of normal proteins mutated RAF is not a complex process, which can include a number of events including membrane translocation, dimerization protein tyrosine phosphorylation by SRC family, the dissociation of protein kinase inhibitors and RAF, together with RAF scaffoldingB the gene in the MAPK cascade in melanomas mutated, wherein. 60% of advanced tumors, the constitutively active mutant protein Activating BRAF mutations are acquired, somatic and zygotic contribution events are not inherited in families. W While more than 65 different mutations in more than 30 codons RAF B, a single base are T missense substitution of a present that changed Valine for glutamic Acid