Selumetinib

Selumetinib (AZD6244) is a second-generation, orally available, potent and selective ATP non-competitive inhibitor of MEK 1/2. In direct assays, AZD6244 selectively inhibits purified active MEK1 and MEK2 with an IC(50) of 14nM, and AZD6244 has reported IC(50) values of < 100nm for MEK1 in ELISA assays and in bindings assays against recombinant domains of MEK2, Kd values were 53nM for AZD6244. AZD6244 demonstrated very effective anti-proliferation effects against several different cell lines with IC(50) values ranging from a low of 3nM to < 1µM depending upon the cell system used, and the compound inhibits basal and growth factor-stimulated phosphorylation of ERK1/ 2 with IC(50) concentrations < 40nM. AZD6244 has demonstrated potent dose-dependent antitumor activity against a panel of mouse xenograft models of colorectal, pancreatic, liver, skin, and lung cancer, and inhibition of tumor growth was found to correlate with the reduction of phospho-ERK1/2 levels in tumors.