Biological Activity
Trametinib DMSO solvate is a potent MEK inhibitor that specifically inhibits MEK1/2, with an IC50 value of about 2 nM.
In Vitro
In BRAF mutant SK-MEL-28 cells and KRAS mutant HCT116 cells, Trametinib (GSK1120212) DMSO solvate causes dose-dependent inhibition of ERK1/2 phosphorylation as well as dose-dependent growth inhibition. In both SK-MEL-28 and HCT116 cells, Trametinib DMSO solvate inhibits 50% p-ERK1/2 at nearly equivalent concentrations (0.8 and 1.8 nM, respectively). However, as the slopes of the curves reflect, in SK-MEL-28 cells, Trametinib DMSO solvate inhibits 90% p-ERK1/2 at a lower concentration (3.4 nM) than in HCT116 (33.3 nM). Furthermore, in both cell lines, 50% growth inhibition is only achieved at concentrations Trametinib DMSO solvate that produces near complete ERK1/2 inhibition (85 and 90%, respectively)[2].
In Vivo
Trametinib (GSK1120212) DMSO solvate is evaluated in vivo in an A549 (KRAS mutant cell line) xenograft model, orally dosing daily for 21 days (qd×21). In this study, near complete tumor growth inhibition is observed at 5.0 and 2.5 mg/kg [92 and 87% tumor growth inhibition (TGI), respectively] and to a lesser degree at 0.5 and 0.1 mg/kg (62 and 58% TGI). Although 5 mg/kg is the maximally tolerated dose (MTD) in this study, 3 mg/kg is the typically observed MTD. Dose-dependent antitumor activity with Trametinib DMSO solvate treatment has been similarly reported for several other KRAS and BRAF mutant tumor models[2].
References & source
Published experimental findings depend on the model and assay conditions. They do not guarantee equivalent performance in every application. For laboratory research use only.
