RO4987655

RO4987655 is an orally active and highly selective MEK inhibitor with an IC 50 of 5.2 nM for inhibition of MEK1 / MEK2 . In Vitro RO4987655 potently inhibits mitogen-activated protein kinase signaling pathway activation and tumor cell growth, with an in vitro IC 50 of 5.2 nM for inhibition of MEK1/2. RO4987655 inhibits proliferation of NCI-H2122 cells in a dose-dependent manner with an IC 50 value of 0.0065 μM. RO4987655 at doses ranging from 0.1 to 1.0 μM suppresses pERK1/2 already at 2 h after the start of treatment. MCE has not independently confirmed the accuracy of these methods. They are for reference only. In Vivo Single-agent oral administration of RO4987655 (CH4987655) results in complete tumor regressions in xenograft models. RO4987655 is rapidly absorbed with a t max of ~1 h. Exposures are dose proportional from 0.5 to 4 mg. The disposition is biphasic with a terminal t 1/2 of ~25 hr. Intersubject variability is low, 9% to 23% for C max and 14% to 25% for area-under-the-curve (AUC). pERK inhibition is exposure dependent and is greater than 80% inhibition at higher doses. The pharmacokinetic-pharmacodynamic relationship is characterized by an inhibitory E max model (E max ~100%; IC 50 40.6 ng/mL) using nonlinear mixed-effect modeling . 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. PET imaging shows that [ 18 F] FDG uptake in the xenografts decreases within 24 h (day 1) from the administration of RO4987655. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Cell Assay 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%CO 2 . 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. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal administration Mice Female athymic nude mice Balb nu/nu , age 5 to 6 weeks (18 to 22 g) are used. NCI-H2122 cells (4×10 6 /mouse) are inoculated subcutaneously in the right flank of Balb-nu/nu mice. Once tumors are established (100 to 200 mm 3 ), mice are randomized into groups with similar mean tumor volumes at the start of the study. 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 . Tumor volume and body weight are measured on days 0 (baseline), 1, 2, 3, and 9 of [18F] FDG-PET imaging. Tumor growth inhibition is calculated . aladdin has not independently confirmed the accuracy of these methods. They are for reference only. Form:Solid IC50& Target:MEK1 5.2 nM (IC 50 ) MEK2 5.2 nM (IC 50 )

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