Size | Price | Stock | Qty |
---|---|---|---|
10mg |
|
||
25mg |
|
||
50mg |
|
||
100mg |
|
||
250mg |
|
||
500mg |
|
||
1g |
|
||
Other Sizes |
|
Purity: =99.29%
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.
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 |
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
|
Related CAS # |
Trametinib (DMSO solvate);1187431-43-1;Trametinib-d4;Trametinib-13C6;Trametinib-13C,d3;2712126-59-3
|
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 (In Vitro) |
|
|||
---|---|---|---|---|
Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.06 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.06 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: 4% DMSO+corn oil: 3mg/mL Solubility in Formulation 4: 6.67 mg/mL (10.84 mM) in 0.5%HPMC 1%Tween80 (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. |
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.
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.
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 |
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. td> |
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. td> |
The combination of GSK2118436 and GSK1120212 is effective in the A375-resistant clones. Mol Cancer Ther . 2012 Apr;11(4):909-20. td> |
A375 resistant clones respond to GSK2126458 in combination with GSK2118436 or GSK1120212. Mol Cancer Ther . 2012 Apr;11(4):909-20. td> |