1. Materials information
Names
| Name |
trametinib dimethyl sulfoxide
|
| Synonym |
More Synonyms
|
Trametinib (DMSO solvate) Biological Activity
| Description |
Trametinib DMSO solvate is a potent MEK inhibitor that specifically inhibits MEK1/2, with an IC50 value of about 2 nM. |
| Related Catalog |
Signaling Pathways >>
MAPK/ERK Pathway >>
MEK
Research Areas >>
Cancer
|
| Target |
MEK1:2 nM (IC50)
MEK2:2 nM (IC50)
|
| In Vitro |
In BRAF mutant SK-MEL-28 cells and KRAS mutant HCT116 cells,
Trametinib (GSK1120212) DMSO solvate causes dose-dependent inhibition of
ERK1/2 phosphorylation as well as dose-dependent growth inhibition. In
both SK-MEL-28 and HCT116 cells, Trametinib DMSO solvate inhibits 50%
p-ERK1/2 at nearly equivalent concentrations (0.8 and 1.8 nM,
respectively). However, as the slopes of the curves reflect, in
SK-MEL-28 cells, Trametinib DMSO solvate inhibits 90% p-ERK1/2 at a
lower concentration (3.4 nM) than in HCT116 (33.3 nM). Furthermore, in
both cell lines, 50% growth inhibition is only achieved at
concentrations Trametinib DMSO solvate that produces near complete
ERK1/2 inhibition (85 and 90%, respectively)[2].
|
| In Vivo |
Trametinib (GSK1120212) DMSO solvate is evaluated in vivo in an
A549 (KRAS mutant cell line) xenograft model, orally dosing daily for 21
days (qd×21). In this study, near complete tumor growth inhibition is
observed at 5.0 and 2.5 mg/kg [92 and 87% tumor growth inhibition (TGI),
respectively] and to a lesser degree at 0.5 and 0.1 mg/kg (62 and 58%
TGI). Although 5 mg/kg is the maximally tolerated dose (MTD) in this
study, 3 mg/kg is the typically observed MTD. Dose-dependent antitumor
activity with Trametinib DMSO solvate treatment has been similarly
reported for several other KRAS and BRAF mutant tumor models[2].
|
| Cell Assay |
SK-MEL-28, and HCT116 cell lines are plated in triplicate 96 well
microtitre plates at 5000 cells per well in culture media. Trametinib
dissolved in DMSO or negative control (0.1% DMSO) are added the
following day and one plate is harvested with 50 μL of CellTiter-Glo for
a time 0 (T=0) measurement. Remaining duplicate cell plates are
typically incubated for 72 h. Cells are then lysed with 50 μL
CellTiter-Glo, and chemiluminescent signal is read on the Wallac
EnVision 2100 plate reader. For measurement of cellular ERK1/2
phosphorylation, cells are seeded and treated with Trametinib, and lysed
after 72 h in Tris lysis buffer supplemented with phosphatase and
protease inhibitors. All samples are analyzed with a phospho-ERK1/2
ELISA. Plates are read on MSD.SI6000 and curves are analyzed using the
XLfit curve-fitting tool. For comparison of the growth assay curve and
pERK1/2 assay curve, data are background subtracted and normalized to
the vehicle treatment control[2].
|
| Animal Admin |
Mice[2] A549 (human non-small cell lung carcinoma) model is
established from cells grown in tissue culture and harvested aseptically
using a trypsin digest. Female athymic mice (strain nu/nu) are injected
subcutaneously with between 5×106 and 107 cells in 50% martigel. Tumors
are allowed to establish for one to four weeks before use. Trametinib
is administered orally at the indicated doses in 0.2 mL/20 g by weight.
Tumors are measured twice weekly using Vernier calipers. Antitumor
activity is defined as tumor growth inhibition representing the % volume
differential in tumor growth between the treated and control tumors at
the time vehicle tumors exceeded a volume of 1000 mm3.
|
| References |
[1]. Yamaguchi
T, et al. Suppressive effect of an orally active MEK1/2 inhibitor in
two different animal models for rheumatoid arthritis: a comparison with
leflunomide. Inflamm Res, 2012, 61(5), 445-454. [2]. Abe
H, et al. Discovery of a Highly Potent and Selective MEK Inhibitor:
GSK1120212 (JTP-74057 DMSO Solvate). ACS Med Chem Lett. 2011 Feb
28;2(4):320-4.
|
Chemical & Physical Properties
| Molecular Formula |
C28H29FIN5O5S |
| Molecular Weight |
693.528 |
| Exact Mass |
693.091797 |
| PSA |
146.90000 |
| LogP |
5.52300 |
| Storage condition |
2-8℃ |
2. Packaging of materials
For powders: normal is 25kgs/Drum or bag, or larger/smaller package as request.
For liquids: normal 25kgs/drum, 180-300kgs/bucket, or IBC, determined by the nature of the product.
Or smaller package 1kg/bottle, 10kgs/bottle as request.
3. Shipping & Delivery
Provide door to door service
Suitable for goods under 50kg
Delivery: 3-7 days
Cost: low cost
Provide airport to airport service
Suitable for goods over 50kg
Delivery: 3-14 days
Cost: high cost
Provide seaport to seaport service
Suitable for goods over 100kg
Delivery: 2-45 days
Cost: low cost
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