| GSK1120212 is a selective and highly potent MEK1 and MEK2 inhibitor with IC50 values of 1.8 and 0.92 nM, respectively. GSK1120212 potently inhibits the phosphorylation of MBP regardless of the isotype of Raf and MEK, with IC50 values ranging from 0.92 to 3.4 nM. However, GSK1120212 has no inhibition of the kinase activities of c-Raf, B-Raf, ERK1 and ERK2. In vitro, GSK1120212 inhibits the growth of human colorectal cancer cell lines HT-29, Colo205, HCT-15, HCT-116 and LS-174T with IC50 values of 0.48, 0.52, 174, 5.7 and 4.1 nM, respectively.[1] In both SK-MEL-28 and HCT116 cells, GSK1120212 inhibits 50% p-ERK1/2 at nearly equivalent concentrations (0.8 and 1.8 nM, respectively). In vivo in an A549 (KRAS mutant cell line) xenograft model, GSK1120212 treatment has near complete tumor growth inhibition with 92 and 87% TGI at 5.0 and 2.5 mg/kg, respectively.[2] In vivo, GSK1120212 (0.3 mg/kg and 1 mg/kg) is also effective in inhibiting the HT-29 xenograft growth, and 1 mg/kg of GSK1120212 blocks the tumor increase almost completely. In the same established tumor tissues, GSK1120212 (1 mg/kg) completely inhibits the phosphorylation of ERK1/2 and upregulates both p15INK4b and p27KIP1 protein levels.[1] In addition, the BRAF-mutant Colo205, A-375P (F11), and HT29 models, GSK1120212 (3 mg/kg) shows significant mean TGI of 85%, 80%, and 87%, respectively, with multiple complete and partial tumor regressions.[3] |
