Trametinib (GSK1120212)

Catalog No.S2673

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

Cited by 47 publications:

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Quality Control & MSDS

Related Compound Libraries

Trametinib (GSK1120212) is available in the following compound libraries:

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Product Information

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  • Research Area
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  • Combination Therapy
    Combination Therapy

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 pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
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 2016-07-30)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02342600 Not yet recruiting Gastrointestinal Stromal Tumors Sarcoma Alliance for Research through Collaboration|Novartis January 2017 Phase 2
NCT02447939 Not yet recruiting Melanoma GlaxoSmithKline September 2016 Phase 1
NCT02780128 Recruiting Neuroblastoma|Cancer Yael P Mosse|Novartis Pharmaceuticals|Foundation Medicine  ...more Yael P Mosse|Novartis Pharmaceuticals|Foundation Medicine|Childrens Hospital of Philadelphia July 2016 Phase 1
NCT02672358 Not yet recruiting Non-Small-Cell Lung Cancer Novartis Pharmaceuticals|Novartis July 2016 Phase 2
NCT02642042 Recruiting Recurrent Non-Small Cell Lung Carcinoma|Stage IV Non-Small Cell Lung Cancer National Cancer Institute (NCI) July 2016 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 22 mg/mL warming (35.74 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 4% DMSO+corn oil 3mg/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

Frequently Asked Questions

  • Question 1
    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.

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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