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

Alias: JTP-74057; GSK 1120212 GSK1120212; GSK-1120212; JTP74057; Trametinib. Trade name: Mekinist
Cat No.:V0446 Purity: =99.29%
Mirdametinib (PD-0325901) is a novel, potent, selective, orally bioavailable and non ATP-competitive inhibitor of the mitogen-activated protein kinase MEK with IC50 of 0.33 nM in cell-free assays, roughly 500-fold more potent than CI-1040 on phosphorylation of ERK1 and ERK2.
Trametinib (GSK-1120212; JTP-74057; Mekinist) Chemical Structure CAS No.: 871700-17-3
Product category: MEK
This product is for research use only, not for human use. We do not sell to patients.
Size Price Stock Qty
10mg
25mg
50mg
100mg
250mg
500mg
1g
Other Sizes

Other Forms of Trametinib (GSK-1120212; JTP-74057; Mekinist):

  • Trametinib DMSO solvate
  • Trametinib-13C,d3
Official Supplier of:
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Alternate Text
Top Publications Citing lnvivochem Products
Purity & Quality Control Documentation

Purity: =99.29%

Purity: ≥98%

Product Description

Trametinib (GSK1120212; JTP74057; Trade name: Mekinist), an FDA-approved anti-melanoma medication, is a novel, highly specific, and orally bioactive MEK1/2 inhibitor with potential antineoplastic activity. In cell-free assays, it inhibits MEK1/2 with IC50 values of 0.92 nM/1.8 nM and exhibits little to no inhibition of other kinases like c-Raf, B-Raf, and ERK1/2. Trametinib was initially thought to be a p15 inductive substance, but it was later discovered to be an allosteric inhibitor of MEK kinase. When used against MEK1 and MEK2 kinase, trametinib exhibits ATP non-competitive inhibition. Trametinib binds to and specifically inhibits MEK 1 and 2, which prevents growth factor-mediated cell signaling and cellular proliferation in a variety of cancers. The RAS/RAF/MEK/ERK signaling pathway, which controls cell growth, is activated by the dual specificity threonine/tyrosine kinases MEK 1 and 2. These kinases are frequently upregulated in different cancer cell types. On May 29, 2013, the FDA granted Trametinib approval to treat melanoma.

Biological Activity I Assay Protocols (From Reference)
Targets
MEK1 (IC50 = 0.92 nM); MEK2 (IC50 = 1.8 nM)
ln Vitro
GSK1120212 has an IC50 range of 0.92 nM to 3.4 nM and inhibits the phosphorylation of MBP regardless of the isotypes of Raf and MEK. c-Raf, B-Raf, ERK1 and ERK2 are not inhibited by GSK1120212's kinase activity. Furthermore, the other 98 kinases are not significantly inhibited by GSK1120212 in a significant way. The human colorectal cancer cell lines are effectively inhibited by GSK1120212. The cells with the highest sensitivity to GSK1120212 have IC50 values of 0.48 nM and 0.52 nM, respectively, and are known to have a constitutively active B-Raf mutant in HT-29 and COLO205. With an IC50 range of 2.2–174 nM, the cell lines with the K-Ras mutation exhibit a wide range of sensitivity to GSK1120212. The wild-type gene in both B-Raf and K-Ras is present in COLO320 DM cells, which are resistant to GSK1120212 even at 10 μM. All sensitive cell lines experience cell-cycle arrest at the G1 phase after a 24-hour treatment with GSK1120212. p15INK4b and/or p27KIP1 are consistently upregulated by GSK1120212 treatment in the majority of colorectal cancer cell lines. ERK phosphorylation by GSK1120212 is inhibited in all susceptible cell lines. Both HT-29 and COLO205 cells experience apoptosis induction from GSK1120212; however, COLO205 cells are more vulnerable to this induction than HT-29 cells are. [1] Peripheral blood mononuclear cells (PBMCs) cannot produce tumor necrosis factor or interleukin-6 because GSK1120212 inhibits this process. [2]
ln Vivo
GSK1120212 can effectively stop the growth of the HT-29 xenograft when given orally at doses of 0.3 mg/kg or 1 mg/kg once daily for 14 days. At doses of 1 mg/kg, the tumor growth is almost entirely stopped. A single oral dose of 1 mg/kg GSK1120212 completely inhibits the phosphorylation of ERK1/2 in the tissues of established tumors, and after 14 days of treatment, the levels of the proteins p15INK4b and p27KIP1 are both increased. Tumor regression is seen in the COLO205 xenograft model even at a dose of 0.3 mg/kg. Four out of six mice receiving a dose of 1 mg/kg experience a complete regression, in which the tumor has regressed to the point where its volume is no longer detectable. [1] Adjuvant-induced arthritis (AIA) and type II collagen-induced arthritis (CIA) in Lewis rats or DBA1/J mice, respectively, are almost completely suppressed after administration of GSK1120212 at 0.1 mg/kg. [2]
Enzyme Assay
The active form of B-Raf/c-Raf, unphosphorylated MEK1/MEK2, and ERERK2, as well as non-phosphorylated myelin basic protein (MBP), are combined with MOPS buffer containing 12.5 mM MgCl2 and 10 μM ATP in the presence of varying concentrations of GSK1120212. The anti-phospho-MBP antibody can spot MBP that has been phosphorylated.
Cell Assay
In 96-well tissue culture plates, exponentially growing cells are precultured for 24 hours before being exposed to GSK1120212. An in vitro toxicology assay kit based on sulforhodamine B measures cell growth. Both adherent and floating cells are collected for the apoptosis assay and fixed with 70% ethanol. The cells are then washed with PBS, suspended in 100 μg/mL RNase and 25 μg/mL propidium iodide (PI), and heated to 37 °C for 30 minutes while kept in the dark. The Cytomics FC500 or Guava EasyCyte plus flow cytometer is used to measure the DNA content of each individual cell.
Animal Protocol
Mice: The mice used are BALB/c-nu/nu females. HT-29 cells or COLO205 cells suspended in ice-cold HBSS (-) are subcutaneously injected into the right flank of the mice on day 0 at a density of 5×106 cells/100 µL/site or 1×106 cells per 100 µL, respectively. When the mean tumor volume reaches 100 mm3, the acetic acid-solvated form of Trametinib (JTP-74057, 0.3 mg/kg, or 1 mg/kg) is dissolved in 10% Cremophor EL-10% PEG400 and given orally once daily for 14 days. Two weeks after the start of dosing, the tumor's length [L(mm)] and width [W(mm)] are measured using a microgauge, and the tumor's volume is calculated using the formula tumor volume (mm3)=L×W×W/2.
References

[1]. Int J Oncol . 2011 Jul;39(1):23-31.

[2]. Inflamm Res . 2012 May;61(5):445-54.

[3]. Mol Cancer Ther . 2012 Apr;11(4):909-20.

[4]. Clin Cancer Res . 2012 Aug 15;18(16):4345-55.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C26H23FIN5O4
Molecular Weight
615.39
Exact Mass
615.08
Elemental Analysis
C, 50.74; H, 3.77; F, 3.09; I, 20.62; N, 11.38; O, 10.40
CAS #
871700-17-3
Appearance
white solid powder
SMILES
CC1=C2C(=C(N(C1=O)C)NC3=C(C=C(C=C3)I)F)C(=O)N(C(=O)N2C4=CC=CC(=C4)NC(=O)C)C5CC5
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)
Chemical Name
N-[3-[3-cyclopropyl-5-(2-fluoro-4-iodoanilino)-6,8-dimethyl-2,4,7-trioxopyrido[4,3-d]pyrimidin-1-yl]phenyl]acetamide
Synonyms
JTP-74057; GSK 1120212 GSK1120212; GSK-1120212; JTP74057; Trametinib. Trade name: Mekinist
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
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: 3mg/mL
 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 1.6250 mL 8.1249 mL 16.2499 mL
5 mM 0.3250 mL 1.6250 mL 3.2500 mL
10 mM 0.1625 mL 0.8125 mL 1.6250 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

Calculator

Molarity Calculator allows you to calculate the mass, volume, and/or concentration required for a solution, as detailed below:

  • Calculate the Mass of a compound required to prepare a solution of known volume and concentration
  • Calculate the Volume of solution required to dissolve a compound of known mass to a desired concentration
  • Calculate the Concentration of a solution resulting from a known mass of compound in a specific volume
An example of molarity calculation using the molarity calculator is shown below:
What is the mass of compound required to make a 10 mM stock solution in 5 ml of DMSO given that the molecular weight of the compound is 350.26 g/mol?
  • Enter 350.26 in the Molecular Weight (MW) box
  • Enter 10 in the Concentration box and choose the correct unit (mM)
  • Enter 5 in the Volume box and choose the correct unit (mL)
  • Click the “Calculate” button
  • The answer of 17.513 mg appears in the Mass box. In a similar way, you may calculate the volume and concentration.

Dilution Calculator allows you to calculate how to dilute a stock solution of known concentrations. For example, you may Enter C1, C2 & V2 to calculate V1, as detailed below:

What volume of a given 10 mM stock solution is required to make 25 ml of a 25 μM solution?
Using the equation C1V1 = C2V2, where C1=10 mM, C2=25 μM, V2=25 ml and V1 is the unknown:
  • Enter 10 into the Concentration (Start) box and choose the correct unit (mM)
  • Enter 25 into the Concentration (End) box and select the correct unit (mM)
  • Enter 25 into the Volume (End) box and choose the correct unit (mL)
  • Click the “Calculate” button
  • The answer of 62.5 μL (0.1 ml) appears in the Volume (Start) box
g/mol

Molecular Weight Calculator allows you to calculate the molar mass and elemental composition of a compound, as detailed below:

Note: Chemical formula is case sensitive: C12H18N3O4  c12h18n3o4
Instructions to calculate molar mass (molecular weight) of a chemical compound:
  • To calculate molar mass of a chemical compound, please enter the chemical/molecular formula and click the “Calculate’ button.
Definitions of molecular mass, molecular weight, molar mass and molar weight:
  • Molecular mass (or molecular weight) is the mass of one molecule of a substance and is expressed in the unified atomic mass units (u). (1 u is equal to 1/12 the mass of one atom of carbon-12)
  • Molar mass (molar weight) is the mass of one mole of a substance and is expressed in g/mol.
/

Reconstitution Calculator allows you to calculate the volume of solvent required to reconstitute your vial.

  • Enter the mass of the reagent and the desired reconstitution concentration as well as the correct units
  • Click the “Calculate” button
  • The answer appears in the Volume (to add to vial) box
In vivo Formulation Calculator (Clear solution)
Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)
Step 2: Enter in vivo formulation (This is only a calculator, not the exact formulation for a specific product. Please contact us first if there is no in vivo formulation in the solubility section.)
+
+
+

Calculation results

Working concentration mg/mL;

Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.

(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
             (2) Be sure to add the solvent(s) in order.

Clinical Trial Information
NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT03363217 Active
Recruiting
Drug: Trametinib Plexiform Neurofibroma
Low-grade Glioma
St. Justine's Hospital August 16, 2018 Phase 2
NCT03501368 Active
Recruiting
Drug: Ceritinib
Advanced Melanoma
Melanoma
Low-grade Glioma
H. Lee Moffitt Cancer Center
and Research Institute
June 27, 2018 Phase 1
NCT04439318 Active
Recruiting
Drug: Trametinib Dimethyl
Sulfoxide
Advanced Lymphoma
Refractory Lymphoma
National Cancer Institute
(NCI)
February 25, 2016 Phase 2
NCT03085056 Active
Recruiting
Drug: Trametinib
Drug: Paclitaxel
Anaplastic Thyroid Cancer Memorial Sloan Kettering Cancer
Center
March 15, 2017 Phase 2
NCT03741101 Active
Recruiting
Drug: Trametinib Child
Neurofibromatosis 1
Neurofibroma, Plexiform
Region Skane June 10, 2019 Phase 2
Biological Data
  • Acquired resistance of A375 clones to GSK2118436. A, structures of the BRAF inhibitors GSK2118436 and PLX4032, MEK inhibitor GSK1120212, and PI3K/mTOR inhibitor GSK2126458. Mol Cancer Ther . 2012 Apr;11(4):909-20.
  • MEK mutation reduces sensitivity in A375 cells. A, front and top views of a MEK1 model showing relative positions of GSK1120212 (yellow), ADP, helix A, Gln56, and Lys59. Mol Cancer Ther . 2012 Apr;11(4):909-20.
  • The combination of GSK2118436 and GSK1120212 is effective in the A375-resistant clones. Mol Cancer Ther . 2012 Apr;11(4):909-20.
  • A375 resistant clones respond to GSK2126458 in combination with GSK2118436 or GSK1120212. Mol Cancer Ther . 2012 Apr;11(4):909-20.
Contact Us