Ro 5126766

Ro 5126766 is a dual inhibitor of MEK1 (IC₅₀ = 160 nM) and Raf kinases (IC₅₀s = 56, 19, and 8.2 nM for C-RAF, B-RAF, and B-RAF^V600E, respectively).¹ It is selective for these kinases over a panel of 254 additional kinases at 10 µM. Ro 5126766 (1 µM) decreases MEK and ERK phosphorylation in a panel of seven cancer cell lines expressing mutant K-Ras^G13D, K-Ras^Q61K, K-Ras^G12D, H-Ras^G12D, or B-RAF^V600E at 1 µM. It inhibits proliferation of SK-MEL-28, SK-MEL-2, MIA PaCa-2, SW480, and HCT116 cancer cells (IC₅₀s = 65, 28, 40, 46, and 277 nM, respectively) but not A549, HCT15, or PC3 cancer cells (IC₅₀s = >1,000 nM for all).² Oral administration of Ro 5126766 (25 mg/kg four times per day) reduces tumor growth in an HCT116 mouse xenograft model.¹

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1. Ishii, N., Harada, N., Joseph, E.W., et al. Enhanced inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that suppresses feedback reactivation of RAF activity. Cancer Res. 73(13), 4050-4060 (2013).

2. Wada, M., Horinaka, M., Yamazaki, T., et al. The dual RAF/MEK inhibitor CH5126766/RO5126766 may be a potential therapy for RAS-mutated tumor cells. PLoS ONE 9(11), e113217 (2014).