RO4987655 is an orally active and highly selective MEK inhibitor with an IC50 of 5.2 nM. RO4987655 inhibits proliferation of NCI-H2122 cells in a dose-dependent manner with an IC50 value of 0.0065 μM.
In vivo, RO4987655 is rapidly absorbed with a tmax of ~1 h. Female athymic nude mice are randomized into study groups. The tumors size is estimated with digital caliper and PET scans performed on days 0, 1, and 3 with 1.0, 2.5, and 5.0 mg/kg RO4987655. The vehicle treatment does not inhibit the NCI-H2122 tumor xenograft growth over this time frame. In contrast, RO4987655 treatment results in 119% tumor growth inhibition (TGI) at 1.0 mg/kg, 145% TGI at 2.5 mg/kg and 150% TGI at 5.0 mg/kg on day 3.
|Cell lines||human lung adenocarcinoma cell line NCI-H2122|
|Preparation method||The human lung adenocarcinoma cell line NCI-H2122 are maintained in the designated media and indicated concentrations of heat-inactivated fetal bovine serum and L-glutamine. Cells are grown at 37°C in an atmosphere of 5%CO2. Cells are treated with various concentrations of RO4987655 (0.00001, 0.001, 0.1, and 10 μM) for 72 h in 96-well plates and viable cells were quantified with Cell Counting Kit-8.|
|Concentrations||0.00001, 0.001, 0.1, and 10 μM|
|Incubation time||72 h|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
|Solubility||DMSO: ≥ 30 mg/mL|
 Leijen S, et al. Clin Cancer Res. Phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of the MEK inhibitor RO4987655 (CH4987655) in patients with advanced solid tumors.
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