Trametinib (GSK1120212)

Catalog No.S2673 Synonyms: JTP-74057

Trametinib (GSK1120212) Chemical Structure

Molecular Weight(MW): 615.39

Trametinib (GSK1120212) is a highly specific and potent MEK1/2 inhibitor with IC50 of 0.92 nM/1.8 nM in cell-free assays, no inhibition of the kinase activities of c-Raf, B-Raf, ERK1/2.

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Biological Activity

Description Trametinib (GSK1120212) is a highly specific and potent MEK1/2 inhibitor with IC50 of 0.92 nM/1.8 nM in cell-free assays, no inhibition of the kinase activities of c-Raf, B-Raf, ERK1/2.
Features More potent than PD0325901 or AZD6244.
Targets
MEK1 [1]
(Cell-free assay)		 MEK2 [1]
(Cell-free assay)
0.92 nM 1.8 nM
In vitro

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. [1] GSK1120212 blocks tumor necrosis factor-α and interleukin-6 production from peripheral blood mononuclear cells (PBMCs). [2]
Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
Transitional cell carcinoma (TCC) cell lines NYjkUFNWTnWwY4Tpc44h[XO|YYm= NUTCTI5tOjVibl2= NEi5XmY3NTJ2IHi= NX3iVIo3S2GwaX7lJHRESyClZXzsJIxqdmW|IHHy[UB{\W6|aYTpeoUhfG9iTVXLJIlvcGmkaYTpc44> NEjLNJc{OTB2OEW0PC=>
BJAB cells NEDkS5BHfW6ldHnvckBie3OjeR?= NH;JUVYxNjBzzszN NVHPUWpIOjRiaB?= M{TUVlAvODFizszNJJRz[W2ndHnubYIh\W[oZXP0bZZmdHlic4XwdJJme3OnZDD0bIUhTVKNIHj5dIVz[WO2aY\heIlwdiCrbjDCTmFDKGOnbHzzJINifXOnZDDifUB1cGViY3;tZolv\WRidILlZZRu\W62IH;mJGJMVTF{MDDhcoQhTGGwdYPldpRq[i5? NHixXmM{ODl2N{W3Oi=>
Human PDAC cell lines (MIA-PACA, PANC-1, CFPAC-1, PL45, CAPAN-2 and HPAF-II) MoPmSpVv[3Srb36gZZN{[Xl? MV6xNEBvVSCxcjCxNFAhdk1? NILjZ5A{NWSjeYOgc5IhPi2mYYnz NVW4W3JEXGinIHPvcoNmdnS{YYTpc44hd2ZiMUCgcm0hfHKjbXX0bY5q[iClb37zbZN1\W62bImgdJJw\HWlZXSgd4lodmmoaXPhcpQh\GmoZnXy[Y5k\XNiYnX0e4VmdiCpZX\peIlvcWJiYX7kJJRz[W2ndHnubYIh[WyxbnWgZ49ueGG{ZXSgeI8h[2:vYnnuZZRqd25iZ3XmbZRqdmmkIHHu[EB1emGvZYTpcoljKGmwIHHscEBnd3W{IIPlcpNqfGm4ZTDj[YxtKGyrbnXzJEhETlCDQz2xMEBxdDR3LDDDRXBCVi1{IHHu[EBJWEGILVnJLU4hVm9iYXTkbZRqfmViZX\m[YN1KHejczDvZpNmen[nZDDpckB1cGViZ3XmbZRqdmmkIHnud4Vve2m2aY\lJI9zKGW6Y3n0ZZRwenliY3XscEBtcW6nczCoUWlCNVCjY3GgZY5lKFCDTlOtNUk> NX\oR2FEOzB7MkGzOVE>
MDA-MB-231, SW480 and SW1116 cells MmntSpVv[3Srb36gZZN{[Xl? NH7tbJgyODEkgJnuUS=> MWCyOEBp M3OwdZRz[W2ndHnubYIh[2:3bHSg[IVkemWjc3WgXWFRKGyndnXsd{BidmRiaX7obYJqfCCOTVKtbY5lfWOnZDDZRXAhfXC{ZXf1cIF1cW:wIHnuJG1FSS2PQj2yN|EtKFOZMUGxOkBidmRiU2e0PFAh[2WubIO= Mk\NN|A5OzN4NkW=
RG7388-resistant U87MG cells M4fMfGZ2dmO2aX;uJIF{e2G7 M4nM[FExKG6P MWmyOEBp MYDEUXNQ NIfNN2pVemGvZYTpcoljKHS{ZXH0cYVvfCC{ZXT1Z4VlKHSqZTDpcpZie2m4ZTDwbIVvd3S7cHWgc4YhWkd5M{i4JJJme2m|dHHueEBk\Wyucz6= M3vheFMxOjd2OUi0

... Click to View More Cell Line Experimental Data
Assay
Methods Test Index PMID
Western blot
ERRα / IDH3 / c-Myc / Cyclin D1; 

PubMed: 30185207     


WB for ERRα, IDH3A, c-Myc and Cyclin D1 in the HCT116 and SW480 cells treated with the indicated concentrations of trametinib (0–100 nM) or DMSO for 48 h. 

pERK /ERK / pS6 / S6 ; 

PubMed: 29133622     


BRAF/NRAS-WT cell lines were treated with vehicle, ceritinib, trametinib or ceritinib-trametinib for 24h before extraction of protein and Western blot for pERK or pS6. Numbers above pS6 indicate the densitometry measurements expressed as a proportion of total S6. 

β-catenin; 

PubMed: 28422736     


The antibodies against phospho-ERK (p-ERK), total ERK (t-ERK) and β-catenin were used to determine the effect of trametinib on the levels of p-ERK and β-catenin in the indicated cells. GAPDH was used as a loading control.

30185207 29133622 28422736
Growth inhibition assay
Cell proliferation; 

PubMed: 30185207     


Cell proliferation was measured using the Cell Counting Kit-8 (CCK-8) assay in the HCT116 and SW480 cells treated with trametinib at 25 nm, 50 nM and 100 nM for 3 d.

MTT assay; 

PubMed: 26832408     


Percent viability of A549 cells determined by MTT assay plotted on a logarithmic molar dose curve scale. Shown are trametinib and fluvastatin single drug dose curves and fluvastatin dose curve with fixed trametinib dosing.

30185207 26832408
Immunofluorescence
phospho-PR(S345); 

PubMed: 29237804     


IF of the nuclear phospho-PR (S345) in ISHIKAWA cells treated with 10 μM onapristone, 100nM trametinib, or a combination for 24 hours.

β-catenin; 

PubMed: 28422736     


Immunofluorescence assay was used to investigate the effect of trametinib on subcellular localization of β-catenin in NOZ and GBC-SD cells. Red color represents nuclear and cytoplasmic staining of β-catenin, and blue color represents Hoeschst 33342 staining for nuclei. Scale bars, 200 μm.

29237804 28422736
In vivo Oral 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. [1] 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. [2]

Protocol

Kinase Assay:[1]
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Raf-MEK-ERK cascade 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 Research:[1]
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  • Cell lines: HT-29, HCT-15, HCT116, COLO205, LS-174T, SW480, SW620, T84, LoVo and COLO320
  • Concentrations: Dissolved in DMSO, final concentrations ~10 μM
  • Incubation Time: 3 or 4 days
  • Method: 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.
    (Only for Reference)
Animal Research:[1]
- Collapse
  • Animal Models: Female BALB/c-nu/nu mice inoculated subcutaneously with HT-29 or COLO205 cells
  • Formulation: Dissolved in 10% Cremophor EL-10% PEG400
  • Dosages: ~1 mg/kg/day
  • Administration: Orally
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 22 mg/mL warmed (35.74 mM)
Water Insoluble
Ethanol Insoluble
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
4% DMSO+corn oil
For best results, use promptly after mixing. 		3mg/mL

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 615.39
Formula

C26H23FIN5O4
CAS No. 871700-17-3
Storage powder
in solvent
Synonyms JTP-74057

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Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT04111458 Not yet recruiting Drug: BI 1701963|Drug: Trametinib Solid Tumors KRAS Mutation Boehringer Ingelheim October 15 2019 Phase 1
NCT04059224 Recruiting Drug: Trametinib|Drug: Dabrafenib Stage IV Melanoma|Stage III Melanoma Universitair Ziekenhuis Brussel January 28 2019 Phase 2
NCT03668431 Recruiting Drug: Dabrafenib|Drug: Trametinib|Drug: PDR001 Metastatic Colorectal Cancer Massachusetts General Hospital|Novartis|Stand Up To Cancer October 15 2018 Phase 2

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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Frequently Asked Questions

  • Question 1:

    Could you help us with the best way to prepare Trametinib for in vivo i.p. injections?

  • Answer:

    S2673 can be dissovled in 4% DMSO/corn oil at 3 mg/ml clearly.

  • Question 2:

    How to solve the problem that this product didn't dissolve up to 10mM in DMSO at room temperature?

  • Answer:

    The solution can be heated up to 50 degree to help dissolve. Besides, sonication (with a probe sonicator) also helped greatly.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID