Single-agent oral administration of RO4987655 (CH4987655) results in complete tumor regressions in xenograft models. RO4987655 is rapidly absorbed with a tmax of ~1 h. Exposures are dose proportional from 0.5 to 4 mg. The disposition is biphasic with a terminal t1/2 of ~25 hr. Intersubject variability is low, 9% to 23% for Cmax 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 Emax model (Emax ~100%; IC50 40.6 ng/mL) using nonlinear mixed-effect modeling[1]. 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 [18F] FDG uptake in the xenografts decreases within 24 h (day 1) from the administration of RO4987655[2].
In Vitro
RO4987655 potently inhibits mitogen-activated protein kinase signaling pathway activation and tumor cell growth, with an in vitro IC50 of 5.2 nM for inhibition of MEK1/2[1]. RO4987655 inhibits proliferation of NCI-H2122 cells in a dose-dependent manner with an IC50 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[2].
Kinase Assay
Cell Assay
Animal Administration
References
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