RO4987655

A potent and highly selective small-molecule MEK inhibitor with IC50 of 5.2 nM; exhibits anti-proliferation IC50s of 1-10 nM for COLO205 (CRC, Braf V600E), HT29 (CRC, Braf V600E), QG56 (NSCLC, HrasQ61L), MIA PaCa-2 (Panc, Kras G12C) cell lines.Solid Tumors Phase 1 Clinical (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. 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. (In Vivo) :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. 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.

874101-00-5

RO-4987655 | RO 4987655 | CH-4987655 | CH4987655 | CH 4987655 | RG-7167

>98% (HPLC)

DMSO: ≥ 40 mg/mL

O=C (NOCCO) C1=CC (CN2OCCCC2=O) =C (F) C (F) =C1NC3=CC=C (I) C=C3F

C20H19F3IN3O5

565.2816

Storage temperature: -20°C. Stability: ≥ 2 years

For research use only.