RO4987655

RO4987655 is an orally active and highly selective MEK inhibitor with an IC50 of 5.2 nM for inhibition of MEK1/MEK2.

Research Areas >> Cancer

MEK1:5.2 nM (IC50)

MEK2:5.2 nM (IC50)

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].

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].

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[2].

Mice[2] Female athymic nude mice Balb nu/nu, age 5 to 6 weeks (18 to 22 g) are used. NCI-H2122 cells (4×106/mouse) are inoculated subcutaneously in the right flank of Balb-nu/nu mice. Once tumors are established (100 to 200 mm3), 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[2].

[1]. Lee L, et al. The safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of CH4987655 in healthy volunteers: target suppression using a biomarker. Clin Cancer Res. 2009 Dec 1;15(23):7368-74.

[2]. Tegnebratt T, et al. Evaluation of efficacy of a new MEK inhibitor, RO4987655, in human tumor xenografts by [(18)F] FDG-PET imaging combined with proteomic approaches. EJNMMI Res. 2014 Dec;4(1):34.

U0126-EtOH | PD98059 | Trametinib (GSK1120212) | PD0325901 | Selumetinib (AZD6244) | Cobimetinib | MEK162(ARRY-162,ARRY-438162) | PD184352 (CI-1040) | RO 5126766 | Isorhamnetin | AS703026 | RGB-286638 | BIX02188 | BIX02189 | SL-327