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    Trametinib (GSK-1120212; JTP-74057; Mekinist)
    Trametinib (GSK-1120212; JTP-74057; Mekinist)

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0446
    CAS #: 871700-17-3Purity ≥98%

    Description: Trametinib (GSK1120212; JTP74057; Trade name: Mekinist), an FDA approved anti-melanoma drug, is a novel, highly specific and orally bioactive MEK1/2 inhibitor with potential antineoplastic activity. It inhibits MEK1/2 with IC50s of 0.92 nM/1.8 nM in cell-free assays, and shows little/no inhibition against other kinases such as c-Raf, B-Raf, ERK1/2. Trametinib was originally identified as a p15 inductive compound but was later found to be an allosteric inhibitor of MEK kinase.Trametinib exhibits ATP non-competitive inhibition against MEK1 and MEK2 kinase. Trametinib specifically binds to and inhibits MEK 1 and 2, resulting in an inhibition of growth factor-mediated cell signaling and cellular proliferation in various cancers. MEK 1 and 2, dual specificity threonine/tyrosine kinases often upregulated in various cancer cell types, play a key role in the activation of the RAS/RAF/MEK/ERK signaling pathway that regulates cell growth. FDA approved Trametinib for the treatment of melanoma on May 29, 2013.

    References: Int J Oncol. 2011 Jul;39(1):23-31; Inflamm Res. 2012 May;61(5):445-54.

    Related CAS: 1187431-43-1 (Trametinib DMSO solvate)

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    Molecular Weight (MW)615.39
    FormulaC26H23FIN5O4
    CAS No.871700-17-3
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 22 mg/mL (35.7 mM)
    Water: <1 mg/mL
    Ethanol: <1 mg/mL
    Solubility (In vivo)4% DMSO+corn oil: 3 mg/mL
    Synonyms

    JTP-74057; GSK 1120212 GSK1120212; GSK-1120212; JTP74057; Trametinib. Trade name: Mekinist.

    Chemical Name: N-[3-[3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-3,4,6,7-tetrahydro-6,8-dimethyl-2,4,7-trioxopyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl]acetamide

    InChi Key: LIRYPHYGHXZJBZ-UHFFFAOYSA-N

    InChi Code: InChI=1S/C26H23FIN5O4/c1-13-22-21(23(31(3)24(13)35)30-20-10-7-15(28)11-19(20)27)25(36)33(17-8-9-17)26(37)32(22)18-6-4-5-16(12-18)29-14(2)34/h4-7,10-12,17,30H,8-9H2,1-3H3,(H,29,34)

    SMILES Code: CC(NC1=CC=CC(N(C(C(C(N2C3CC3)=O)=C(NC4=CC=C(I)C=C4F)N5C)=C(C)C5=O)C2=O)=C1)=O 


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    In Vitro

    In vitro activity: GSK1120212 inhibits the phosphorylation of MBP regardless of the isotype of Raf and MEK, with IC50 ranging from 0.92 nM to 3.4 nM. GSK1120212 demonstrates no inhibition of the kinase activities of c-Raf, B-Raf, ERK1 and ERK2. In addition, GSK1120212 does not show drastic inhibitory activity against the other 98 kinases. GSK1120212 displays potent inhibitory activity against human colorectal cancer cell lines. HT-29 and COLO205 cells, which are known to have a constitutively active B-Raf mutant, are most sensitive to GSK1120212 with IC50 0.48 nM and 0.52 nM, respectively. The cell lines bearing a K-Ras mutation show a wide range of sensitivity to GSK1120212 with IC50 of 2.2-174 nM. In contrast, COLO320 DM cells, bearing the wild-type gene in both B-Raf and K-Ras, are found to be resistant to GSK1120212 even at 10 μM. GSK1120212 treatment for 24 hours induces cell-cycle arrest at the G1 phase in all sensitive cell lines. Consistently, GSK1120212 treatment leads to upregulation of p15INK4b and/or p27KIP1 in most of the colorectal cancer cell lines. GSK1120212 inhibits constitutive ERK phosphorylation in all sensitive cell lines. GSK1120212 induces apoptosis both in HT-29 and COLO205 cells, but that COLO205 cells are more sensitive to GSK1120212 than HT-29 cells in terms of apoptosis induction. GSK1120212 blocks tumor necrosis factor-α and interleukin-6 production from peripheral blood mononuclear cells (PBMCs).


    Kinase Assay: Non-phosphorylated 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 ERERK2 in 10 μM ATP and 12.5 mM MgCl2 containing MOPS buffer in the presence of various concentrations of GSK1120212. The phosphorylation of MBP is detected by the anti-phospho-MBP antibody.


    Cell Assay:  Exponentially growing cells are precultured in 96-well tissue culture plates for 24 hours and then exposed to GSK1120212. Cell growth is determined by an in vitro toxicology assay kit, sulforhodamine B based. For apoptosis assay, both floating and adherent cells are collected and fixed with 70% ethanol. After washing with PBS, the cells are suspended in 100 μg/mL RNase and 25 μg/mL propidium iodide (PI) and incubated at 37 °C for 30 minutes in the dark. The DNA content of each single cell is determined using the flow cytometer Cytomics FC500 or Guava EasyCyte plus.

    In VivoOral administration of GSK1120212 at 0.3 mg/kg or 1 mg/kg once daily for 14 days is effective in inhibiting the HT-29 xenograft growth, and 1 mg/kg of GSK1120212 almost completely blocks the tumor increase. The phosphorylation of ERK1/2 is completely inhibited in the established tumor tissues by single oral dose of 1 mg/kg GSK1120212, and both p15INK4b and p27KIP1 protein levels are upregulated after 14 days of treatment with GSK1120212. In the COLO205 xenograft model, tumor regression is observed even at a dose of 0.3 mg/kg. At a dose of 1 mg/kg, a complete regression is obtained in 4 out of 6 mice in which the tumor degenerates to the point that tumor volume is not measurable. Administration of GSK1120212 at 0.1 mg/kg almost completely suppresses adjuvant-induced arthritis (AIA) and type II collagen-induced arthritis (CIA) in Lewis rats or DBA1/J mice, respectively.
    Animal modelFemale BALB/c-nu/nu mice inoculated subcutaneously with HT-29 or COLO205 cells
    Formulation & DosageDissolved in 10% Cremophor EL-10% PEG400; 1 mg/kg;  Oral gavage
    References

    Int J Oncol. 2011 Jul;39(1):23-31; Inflamm Res. 2012 May;61(5):445-54.


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    Trametinib (GSK1120212)


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