Trametinib (GSK1120212)

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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Trametinib (GSK1120212) Chemical Structure

Trametinib (GSK1120212) Chemical Structure
Molecular Weight: 615.39

Validation & Quality Control

Product Use Citation(45)

Customer Product Validation(10)

Quality Control & MSDS

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Product Description

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.
Targets MEK1 [1]
(Cell-free assay)
MEK2 [1]
(Cell-free assay)
IC50 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]
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]
Features More potent than PD0325901 or AZD6244.

Protocol(Only for Reference)

Kinase Assay: [1]

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 Assay: [1]

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.

Animal Study: [1]

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

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Yamaguchi T, et al. Int J Oncol, 2011, 39(1), 23-31.

[2] Yamaguchi T, et al. Inflamm Res, 2012, 61(5), 445-454.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2015-06-27)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02292732 Not yet recruiting Cancer GlaxoSmithKline September 2015 Phase 1
NCT02140840 Not yet recruiting Multiple Myeloma University of Arkansas August 2015 Phase 2
NCT02465060 Not yet recruiting Adult Lymphoma|Adult Solid Neoplasm|Advanced Malignant Neoplasm|Refractory Malignant Neoplasm National Cancer Institute (NCI) July 2015 Phase 2
NCT02447939 Not yet recruiting Melanoma GlaxoSmithKline June 2015 Phase 1
NCT02428270 Not yet recruiting Pancreatic Cancer|Adenocarcinoma University Health Network, Toronto|GlaxoSmithKline June 2015 Phase 2

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Chemical Information

Download Trametinib (GSK1120212) SDF
Molecular Weight (MW) 615.39
Formula

C26H23FIN5O4

CAS No. 871700-17-3
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms JTP-74057
Solubility (25°C) * In vitro DMSO 100 mg/mL warmed (162.49 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol 15 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* 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 Name N-(3-(3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide

Customer Product Validation (10)


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Rating
Source Nature 2014 510(7504), 283-7. Trametinib (GSK1120212) purchased from Selleck
Method HE staining, IHC
Cell Lines Smyd3 mutant mice
Concentrations 1 mg/kg
Incubation Time 7 days
Results Administration of Kras and Kras;Smyd3 mutant mice with a normal dose of Trametinib blocked tumorigenesis in both strains, though phosphorylation of ERK1/2 was still lower in mice depleted of SMYD3. Notably, a low dose Trametinib regimen, which only partially inhibited pERK1/2 levels and the formation of neoplastic lesions in Kras mutant mice, was sufficient to block tumorigenesis and ERK1/2 activation in Smyd3 knockouts.

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Rating
Source Cancer Discov 2014 4(2), 232-45. Trametinib (GSK1120212) purchased from Selleck
Method Immunofluorescence
Cell Lines 5XMYC cells
Concentrations 100 nM
Incubation Time 4, 24, 48 h
Results Treatment of 5XMYC cells with a MEK inhibitor (GSK1120212/trametinib) resulted in the formation of polarized normal acini, as observed by immunofluorescence for basal (CK5, vimentin), luminal (CK8, e-cadherin), and a tight-junction marker (ZO-1).

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Source Cell Res 2015 25(5), 561-73. Trametinib (GSK1120212) purchased from Selleck
Method Immunoblot analysis
Cell Lines PANC-1 cells
Concentrations 10 uM
Incubation Time 30 h
Results It treated PANC-1 cells with trametinib, a MEK inhibitor, and the phosphorylation of endogenous FBW7 in PANC-1 cells was also significantly reduced when detected with the specific p-FBW7 antibody.

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Source Nat Commun 2015 5, 5694. Trametinib (GSK1120212) purchased from Selleck
Method Crystal violet
Cell Lines SKMel28 cells
Concentrations 5 uM
Incubation Time 10 d
Results Functional analyses of MEK1 and MEK2 mutant proteins with mutations in equivalent residues-MEK1C121S versus MEK2C125S-confirmed that, although both mutant MEK proteins displayed elevated ERK kinase activity, relative to the wild-type MEK protein , only expression of the MEK2C125S mutant (found in two combination-resistant Progs; patients C1 and C3) was associated with significant levels of phosphorylated retinoblastoma protein (a marker of cell proliferation), phosphorylated ERK and colony growth in the presence of combined dabrafenib and trametinib.

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Source EMBO Rep 2015 16(1), 87-96. Trametinib (GSK1120212) purchased from Selleck
Method Immunofluorescence
Cell Lines 16HBE cells
Concentrations 500 nM
Incubation Time 4 d
Results 16HBE cells were cultured to confluence and then deprived of calcium to disrupt cell-cell contacts. Rapid, synchronous junction reformation was initiated by the readdition of calcium for 4 h, with or without the MEK inhibitor (GSK1120212). Under these conditions, junctions form normally in both control and MEK-inhibited cells.

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Source J Neurosci 2012 32, 4887-900. Trametinib (GSK1120212) purchased from Selleck
Method Western blot
Cell Lines neurons
Concentrations 0.1 μM
Incubation Time
Results RDEA119 (1 μM) or JTP-74057 (0.1 μM) abolished the effects of G1 on the DAPK1 ( F (5, 24) 26.53, p < 0.01, Tukey’s test; p = 0.017, NMDA plus G1 plus RDEA vs NMDA plus G1; p < 0.01, NMDA plus G1 plus JTP vs NMDA plus G1) and NR2B phosphorylation (F(5, 24) 19.35, p < 0.01, Tukey’s test; p = 0.014, NMDA plus G1 plus RDEA vs NMDA plus G1; p = 0.046, NMDA plus G1 plus JTP vs NMDA plus G1.

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Source Mol Cancer Ther 2014 13(12), 3098-106. Trametinib (GSK1120212) purchased from Selleck
Method Immunoblot analysis
Cell Lines OCUM-1, Okajima, SNU-16 cells
Concentrations 0-10 nM
Incubation Time 3 h
Results It examined the phosphorylation levels of ERK1/2 after GSK1120212 exposure (0, 1, 3, 10, and 30 nM) in each GC cell line. Three hours of exposure to GSK1120212 induced a significant decrease in the phosphorylation levels of ERK1/2 in the hypersensitive cell lines (OCUM-1 and Okajima), compared with the level in a non-sensitive cell line (SNU-16).

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Source One customer. Trametinib (GSK1120212) purchased from Selleck
Method Cell growth inhibition assay
Cell Lines Melanoma cell lines
Concentrations 0.00000256-5 μM
Incubation Time 72 h
Results GSK1120212 treatment inhibited Melanoma cells growth in a does-dependent manner.

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Source Trametinib (GSK1120212) purchased from Selleck
Method Western blot analysis/ In vitro colony formation assay
Cell Lines LOX IMVI melanoma cells
Concentrations 0-1 μM
Incubation Time 24 h
Results As it is shown in Figure a, a strong induction of pErbB3, with concomitant increase of pAKT was observed 24 h after cell exposure to the MEK inhibitor. In vitro colony formation assays were run in the presence of growing concentrations of GSK1120212b alone or in combination with a fixed dose of A4. Also in this case, co-treatment with anti-ErbB3 strongly potentiated growth inhibition by the MEK inhibitor (Figure b). when cells were treated w ith suboptimal doses of vemurafenib and GSK1120212b, the addition of A4 was capable to provide a powerful synergis tic inhibition of cell growth (Figure c).

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Source Jonas Nilsson, PhD from University of Gothenburg. Trametinib (GSK1120212) purchased from Selleck
Method Western blot, cell apoptosis assays
Cell Lines Mouse carcinoma cells
Concentrations 1-1000 nM
Incubation Time 16/40 h
Results (A) whereas apoptosis was induced at 40h. (B) Biological effects of the compounds correlated with effects on phosphorylation of the MEK target ERK. (C) IC50 on S-phase and ERK-posphorylation: TAK-733=1-10 nM, GSK1120212=<1 nM.

Product Use Citation (45)

Tech Support & FAQs

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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