Trametinib

SKU: orb1306425

Description

Trametinib is an orally active, ATP-noncompetitive inhibitor of MEK1 and MEK2 (IC50=0.7/0.9 nM). It is widely used in cancer research to study pathways involving cell proliferation and survival, as it can induce autophagy and apoptosis in both in vitro and in vivo models.

Research Area

Pharmacology & Drug Discovery

Key Properties

• CAS Number: 871700-17-3
• MW: 615.4
• Purity: >98%
• Formula: C₂₆H₂₃FIN₅O₄
• SMILES: N(C1=C2C(N(C(=O)N(C2=O)C3CC3)C4=CC(NC(C)=O)=CC=C4)=C(C)C(=O)N1C)C5=C(F)C=C(I)C=C5
• Target: Kinase
• Solubility: Soluble in DMSO (up to 20 mg/ml with warming)

Bioactivity

• Target IC50:
  MEK2:0.92 nM (cell free)|HCT116 cells:1.5 nM (EC50)|MEK1:1.8 nM (cell free)
• In Vivo:
  METHODS: To detect anti-tumor activity in vivo, Trametinib (0.3-1 mg/kg) was orally administered to BALB/c-nu/nu mice bearing human colorectal cancer tumors HT-29 and COLO205 once daily for fourteen days. RESULTS: Trametinib treatment significantly inhibited the growth of human colorectal cancer tumors, indicating antitumor activity in vivo. METHODS: To assay antitumor activity in vivo, Trametinib (5 mg/kg) was injected intraperitoneally three times a week for fourteen days into NSG mice bearing human B-lymphoblastic leukemia tumors KOPN8 and COLO205. RESULTS: Trametinib monotherapy delayed the progression of leukemia, but was not sufficient to prevent leukemia growth.
• In Vitro:
  METHODS: Mouse intrahepatic cholangiocarcinoma cells SB1, LD-1 and human intrahepatic cholangiocarcinoma cells EGI-1 were treated with Trametinib (0-10,000 nM) for 48 h, and cell growth inhibition was detected by MTT. RESULTS: Trametinib dose-dependently inhibited the growth of SB1, LD-1 and EGI-1 cells with IC50 of 41.48 nM, 56.10 nM and 27.89 nM, respectively. METHODS: Human colon cancer cells RKO were treated with Trametinib (200 nmol/L) for 30 h. The expression levels of target proteins were detected by Western Blot. RESULTS: Trametinib significantly reduced the levels of p-ERK and p-AKT. METHODS: Human glioma cells U87 and U251 were incubated with Trametinib (50 nM) for 6-72 h. Apoptosis was detected by Flow Cytometry. RESULTS: Trametinib induced a significant increase in apoptosis in U87 and U251 cells, and Trametinib induced late apoptosis but not early apoptosis in glioma cells.
• Cell Research:
  These cells were maintained in media recommended by the providers. Exponentially growing cells were precultured in 96-well tissue culture plates for 24 h and then exposed to JTP-74057. Cell growth was determined by an in vitro toxicology assay kit, sulforhodamine B based. For combination studies, two compounds were simultaneously added to the HT-29 cells and incubated for 72 h. In the presence of various concentrations of compound A, the 50% inhibitory concentration (IC50) values of compound B were determined. Then, the fixed concentration of compound A versus the IC50 value of compound B was plotted. Conversely, the IC50 values of compound A were determined in the presence of various concentrations of compound B and plotted .
• Animal Research:
  Female BALB/c-nu/nu mice were used. On day 0, HT-29 cells or COLO205 cells suspended in ice-cold HBSS (-) were inoculated subcutaneously into the right flank of the mice at 5x10^6 cells/100 μl/site or 1x10^6 cells/100 μl/site, respectively. The acetic acid-solvated form of JTP-74057 was dissolved in 10% Cremophor EL-10% PEG400 and was administered orally once daily for 14 days from the day when the mean tumor volume reached 100 mm^3. The tumor length [L (mm)] and width [W (mm)] were measured using a micro gauge twice a week after the commencement of dosing, and the tumor volume was calculated using the following formula: tumor volume (mm^3) = L x W x W/2. All procedures relating to the use of animals in this study were reviewed and approved by the Institutional Animal Care and Use Committee of Japan Tobacco .

Storage & Handling

• Storage: -20°C
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

GSK1120212; JTP-74057

Compound Identifiers

PubChem CID

11707110