Trametinib, DMSO Solvate

Soluble in DMSO. This research compound is the DMSO solvate form of trametinib. Trametinib is a selective MEK inhibitor. Trametinib inhibited MEK1/2 kinase activity, prevented Raf-dependent MEK phosphorylation, and produced prolonged p-ERK1/2 inhibition. It blocked the cell growth potently in most tumor lines with mutant BRAF or Ras. In xenograft tumor models, trametinib inhibited tumor growth, possibly by sustained suppression of p-ERK1/2, inhibition of tumor Ki67, and stimulation of p27Kip1/CDKN1B. The largest antitumor effect in vivo was among tumors harboring mutant BRAF or Ras. Gilmartin, A.G., et al. 'GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition.' Clin. Cancer Res. 17: 989-1000 (2011). A phase 1 clinical trial demonstrated substantial clinical activity of trametinib in human melanoma. Falchook, G.S., et al. 'Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial.' Lancet Oncol. 13: 782-789 (2012). Trametinib improved rates of progression-free and overall survival among patients who had metastatic melanoma with a BRAF V600E or V600K mutation when compared with dacarbazine or paclitaxel. Flaherty, K.T., et al. 'Improved survival with MEK inhibition in BRAF-mutated melanoma.' N. Engl. J. Med. 367: 107-114 (2012). Both trametinib and leflunomide can suppress adjuvant-induced arthritis (AIA) and type II collagen-induced arthritis (CIA) development completely. In the CIA model, trametinib, but not leflunomide, inhibited collagen-reactive T-cell proliferation ex vivo, whereas leflunomide, but not trametinib, inhibited anti-collagen antibody production. Yamaguchi, T., 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: 445-454 (2012). For solid tumors, RAF/RAS mutation and the expression of the DUSP6 gene were strong predictors of sensitivity to trametinib. Among hematologic cell lines, acute and chronic myeloid leukemia cell lines were particularly sensitive to trametinib. Jing, J., et al. 'Comprehensive predictive biomarker analysis for MEK inhibitor GSK1120212.' Mol. Cancer Ther. 11: 720-729 (2012). Trametinib had favorable antitumor activities against colorectal cancers in vitro and in vivo. It exhibited an additive or a synergistic effect in combination with other chemotherapy agents including 5-fluorouracil, oxaliplatin, or SN-38. Yamaguchi, T., 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: 23-31 (2011).