Showed that these proteins Being targeted by pharmacological agents or siRNA is highly specific for DCC-2036 the MAPK pathway and h Depends on the RAS mutation status. Tumors that harbor V600EB RAF anf Llig for the inhibition of MEK, but not those harboring mutant RAS are. Therefore B RAF mutation status is a critical factor in selecting musing require MEK inhibitors for the treatment of melanoma. However, a variety of different cancer cell lines with RAS or K, N or W RAS-RAF mutations sensitive to AZD6244 1 mol / L. The majority of cell lines, the mutant RAF B are dependent Ngig of MEK activity t and therefore sensitive to inhibition of MEK. In contrast, the presence of RAS mutation K cells makes them less sensitive to inhibition of MEK, the Nnte from its k RAS involved to initiate signaling through other pathways of carcinogenesis.
Not only that these cells respond AZD6244, but were sensitive to MEK inhibition by CI 1040th In addition, a recent study found that targeting mutant B-RAF Co and MEK1 / 2 may be more effective than inhibition LDN193189 of either protein alone. MEK and is a promising target in melanoma. 2.7. MEK is working therapeutic target in melanoma MEK inhibitors CI 1040, PD0325901 and AZD6244 were developed and pr Clinical animal models and in patients with melanoma go Ren tested. These inhibitors proved the activity t of MEK at low nanomolar concentrations with high selectivity T and reduce tumor growth in animal models. Although CI 1040 appeared promising in phase I studies, the clinical development of this drug was discontinued due to low bioavailability and metabolism, administration of very high doses at regular Strength intervals ends Required.
PD0325901 is a second generation MEK inhibitor with significantly improved pharmaceutical properties. PD0325901 is 50 times st Amplifier against MEK and improved stability t and plasma bioavailability, which then causes more inhibition of MEK, by IC 1040th Even if it is bioavailable and metabolically stable, was toxicity T st Stronger than IC 1040 in Phase I clinical trials, stopped clinical development. Also observed AZD6244, PD0325901 similar encouraging results in phase I trials, but no significant difference when compared to temozolomide in a phase II study. Other MEK1 / 2 inhibitors, which are in clinical trials, go ARRY 162, ARRY 300, AZD6244 AZD8330 and Ren.
ARRY 162 is a novel, non-ATP competitive, potent and selective orally bioavailable, MEK 1/2 inhibitor that has the potential of a variety of malignancies. XL518 is a selective inhibitor of other kinases MEK. Pr Clinical data with XL518 has anti-tumor activity shown t In xenograft studies of melanoma, but no clinical data are available at the moment. Anti-tumorigenic and anti-metastatic effect of U0126, another MEK inhibitor was under in vitro and in vivo use of cell lines melanoma. In cultured cells, U0126 treatment effectively reduced the invasion as PD98059. Mechanistic, U0126 inhibits the phosphorylation of MEK1 / 2, a decrease of urokinase plasminogen activator, matrix metalloproteinase 9 and c June Furthermore intraperitoneal administration of U0126 reduced lung metastasis development in models of lung metastases. Ho