Trametinib DMSO solvate (GSK-1120212 (DMSO solvate);JTP-74057 (DMSO solvate)) 是一种具有口服活性的 MEK 抑制剂，抑制 MEK1 和 MEK2，IC50 约为 2 nM。 Trametinib DMSO solvate 激活自噬并诱导细胞凋亡。
Trametinib (also known as GSK1120212 or JTP 74057), originally identified as a p15 inductive compound, is a novel and potent allosteric inhibitor of MEK kinase, which exhibits ATP non-competitive inhibition against MEK1 and MEK2 kinase. It has demonstrated broad antitumor activities in a variety of tumor xgenograft models, including HT-29 and COLO205 colorectal tumor cell lines. Trametinib induces expression of p15 and p27, reduces cyclin D1 levels, and causes dephosphorylation of RB protein and G1-phase arrest with a reduction of TS expression in HT-29 cells. It also effectively inhibits p-ERK 1/2 resulting in cell growth inhibition in tumor cell lines harboring B-RAF mutant.
Reference
1.Akintunde Akinleye, Muhammad Furqan, Nikhil Mukhi, Pavan Ravella and Delong Liu. MEK and the inhibitors: from bench to bedside. Journal of Hematology & Oncology 2013, 6:27
2.Motoki Watanabe, Yoshihiro Sowa, Mayumi Yogosawa and Toshiyuki Sakai. Novel MEK inhibitor trametinib and other retinoblastoma gene (RB)-reactivating agents enhance efficacy of 5-fluorouracil on human colon cancer cells. Cancer Sci 2013; 104(6): 687-693
| Kinase experiment [1]: | |
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Raf-MEK-ERK cascade kinase assay |
Non-phosphorylated myelin basic protein (MBP) was coated onto an ELISA plate, and the active form of B-Raf/c-Raf was mixed with unphosphorylated MEK1/MEK2 and ERERK2 in 10 μM ATP and 12.5 mM MgCl2 containing MOPS buffer in the presence of various concentrations of Trametinib. The phosphorylation of MBP was detected by the anti-phospho-MBP antibody. |
| Cell experiment [1]: | |
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Cell lines |
HT-29 and COLO205 cells |
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Preparation method |
This compound is soluble in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reaction Conditions |
0, 1, 10 and 100 nM; 0 ~ 4 days |
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Applications |
Trametinib induced apoptosis both in HT-29 and COLO205 cells, but that COLO205 cells were more sensitive to Trametinib than HT-29 cells in terms of apoptosis induction. |
| Animal experiment [1]: | |
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Animal models |
Female BALB/c-nu/nu mice inoculated subcutaneously with HT-29 or COLO205 cells |
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Dosage form |
0.3 or 1 mg/kg; p.o.; q.d., for 14 days |
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Applications |
Oral administration of Trametinib (0.3 or 1 mg/kg, q.d., for 14 days) was effective in inhibiting the HT-29 xenograft growth, and 1 mg/kg of Trametinib almost completely blocked the tumor increase. In the COLO205 xenograft model, tumor regression was observed even at a dose of 0.3 mg/kg. At a dosage of 1 mg/kg, a complete regression was obtained in 4 out of 6 mice in which the tumor degenerated to the point that tumor volume was not measurable. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: [1]. Yamaguchi T, Kakefuda R, Tajima N, Sowa Y, Sakai T. Antitumor activities of JTP-74057 (GSK1120212), a novel MEK1/2 inhibitor, on colorectal cancer cell lines in vitro and in vivo. Int J Oncol. 2011 Jul;39(1):23-31. | |
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