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Trametinib

MCE China：Trametinib

Brand：MedChemExpress (MCE)

Cat. No.HY-10999

CAS：871700-17-3

Synonyms：GSK1120212; JTP-74057

Purity：99.96%

Storage：Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month

Shipping：Room temperature in continental US; may vary elsewhere.

Description：Trametinib (GSK1120212; JTP-74057) is an orally active MEK inhibitor that inhibits MEK1 and MEK2 with IC50s of about 2 nM. Trametinib activates autophagy and induces apoptosis.

In Vitro：Trametinib (GSK1120212;JTP-74057) (0.1-100 nM) blocks tumor necrosis factor-α and interleukin-6 production from peripheral blood mononuclear cells (PBMCs). Trametinib (JTP-74057) inhibits the growth of 9 out of 10 human colorectal cancer cell lines, and they shows cell-cycle arrest at the G1 phase after drug tratment[1]. The combination of GSK2118436 and Trametinib (GSK1120212) effectively inhibits cell growth, decreases ERK phosphorylation, decreases cyclin D1 protein, and increases p27(kip1) protein in the resistant clones[2].

In Vivo：Adjuvant-induced arthritis (AIA) and type II collageninduced arthritis (CIA) development are suppressed almost completely by 0.1 mg/kg of Trametinib (GSK1120212; JTP-74057) or 10 mg/kg of HWA486[1]. Trametinib (0.3 mg/kg, 1 mg/kg, p.o.) is effective in inhibiting the HT-29 xenograft growth in a nude mouse xenograft model[2].

Animal Administration：Mice[2] Female BALB/c-nu/nu mice are used. On day 0, HT-29 cells or COLO205 cells suspended in ice-cold HBSS (-) are inoculated subcutaneously into the right flank of the mice at 5×106 cells/100 µL/site or 1×106 cells/100 µL/site, respectively. The acetic acid-solvated form of Trametinib (JTP-74057, 0.3 mg/kg, 1 mg/kg) is dissolved in 10% Cremophor EL-10% PEG400 and is administered orally once daily for 14 days from the day when the mean tumor volume reached 100 mm3. The tumor length [L(mm)] and width [W(mm)] are measured using a microgauge twice a week after commencement of dosing, and the tumor volume is calculated using the following formula: tumor volume (mm3)=L×W×W/2.

Cell Assay：Cells are treated with various concentrations of Trametinib (JTP-74057) in 100 mm dishes for 3 or 4 days. Both floating and adherent cells are collected and fixed with 70% ethanol. After washing with PBS, the cells are suspended in 100 µL/mL RNase and 25 µL/mL Propidium iodide (PI) and incubated at 37°C for 30 min in the dark. The DNA content of each single cell is determined using the flow cytometer Cytomics FC500 or Guava EasyCyte plus[2].

Kinase Assay：The nonphosphorylated myelin basic protein (MBP) is coated onto an ELISA plate, and the active form of B-Raf/c-Raf is mixed with unphosphorylated MEK1/MEK2 and ERK2 in 10 µM ATP and 12.5 mM MgCl2 containing MOPS buffer in the presence of various concentrations of Trametinib (JTP-74057). The phosphorylation of MBP is detected by the anti-phosphoMBP antibody. Kinase inhibitory activities against a total of 99 kinases are tested at 10 µM ATP[2].

IC50 & Target：MEK1 2 nM (IC50) MEK2 2 nM (IC50)

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References：

[1]. Yamaguchi T, et al. Suppressive effect of an orally active MEK1/2 inhibitor in two different animal models for rheumatoid arthritis: a comparison with HWA486. Inflamm Res, 2012, 61(5), 445-454.  [Content Brief]

[2]. 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, 2011, 39(1), 23-31.  [Content Brief]

[3]. Abe H, et al. Discovery of a Highly Potent and Selective MEK Inhibitor: GSK1120212 (JTP-74057 DMSO Solvate). ACS Med Chem Lett. 2011 Feb 28;2(4):320-4.  [Content Brief]

[4]. Liu H, et al. Identifying and Targeting Sporadic Oncogenic Genetic Aberrations in Mouse Models of Triple Negative Breast Cancer. Cancer Discov. 2018 Mar;8(3):354-369.  [Content Brief]

[5]. Lai J, et al. Elimination of melanoma by sortase A-generated TCR-like antibody-drug conjugates (TL-ADCs) targeting intracellular melanoma antigen MART-1. Biomaterials. 2018 Sep;178:158-169.  [Content Brief]