Trametinib

Trametinib is an inhibitor of MEK1 and -2.¹ It inhibits B-RAF- and C-RAF-induced phosphorylation of MEK1 (IC₅₀s = 3.4 and 1.8 nM, respectively) and MEK2 (IC₅₀s = 1.6 and 0.92 nM, respectively). Trametinib inhibits the growth of two human colorectal cancer cell lines expressing mutant B-RAF (IC₅₀s = 0.48 and 0.52 nM) and seven cell lines expressing mutant K-Ras (IC₅₀s = 2.2-174 nM) but does not inhibit the growth of wild-type COLO 320DM cells expressing both B-RAF and K-Ras (IC₅₀ = >10,000 nM). It reduces tumor growth in HT-29 and COLO 205 mouse xenograft models when used at doses of 0.3 and 1 mg/kg per day. Trametinib (0.03 and 0.1 mg/kg per day) also decreases M. tuberculosis-induced increases in hind paw volume in a rat model of arthritis.² Formulations containing trametinib, in combination with dabrafenib, have been used in the treatment of metastatic mutant B-RAF^V600E melanoma.

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1. Yamaguchi, T., Kakefuda, R., Tajima, N., et al. Antitumor activities of JTP-74057 (GSK1120212), a novel MEK1/2 inhibitor, on colorectal cancer cell lines in vitro and in vivo. Int. J. Oncol. 39(1), 23-31 (2011).

2. Yamaguchi, T., Kakefuda, R., Tanimoto, A., et al. Suppressive effect of an orally active MEK1/2 inhibitor in two different animal models for rheumatoid arthritis: A comparison with leflunomide. Inflamm. Res. 61(5), 445-454 (2012).