Antibodies
Trametinib (GSK1120212)
- 貨號 Cat. No.
- S2673
- 規格 Size
- 5~200mg
- 品牌 Brand
- Selleckchem
Description
Trametinib (GSK1120212)
Trametinib (GSK1120212) is a highly specific and potent MEK1/2 inhibitor with IC50 of 0.92 nM/1.8 nM, no inhibition of the kinase activities of c-Raf, B-Raf, ERK1/2. Phase 3.
| Size | Price | Stock | Quantity | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| |||||||||||||||||||||||
Distributor Tel: +886-2-2827-1197jimmy@new.abscience.com.tw
Biological Activity
| Description | Trametinib (GSK1120212) is a highly specific and potent MEK1/2 inhibitor with IC50 of 0.92 nM/1.8 nM, no inhibition of the kinase activities of c-Raf, B-Raf, ERK1/2. Phase 3. | |||||
|---|---|---|---|---|---|---|
| Targets | MEK1 | MEK2 | ||||
| IC50 | 0.92 nM | 1.8 nM [1] | ||||
| 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 |
|---|---|
| Dosages | ~1 mg/kg/day |
| Administration | Orally |
| Solubility | 30% PEG400/0.5% Tween80/5% propylene glycol, 15 mg/mL |
References
Clinical Trial Information( data from http://clinicaltrials.gov)
| NCT Number | Recruitment | Conditions | Sponsor /Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT01037127 | Completed | Cancer | GlaxoSmithKline | 2009-12 | Phase 2 |
| NCT01248858 | Recruiting | Cancer | GlaxoSmithKline | 2010-12 | Phase 1 |
| NCT01723202 | Recruiting | Follicular Thyroid Cancer|Insular Thyroid Cancer|Papillary Thyroid Cancer|Recurrent Thyroid Cancer | Ohio State University Comprehensive Cancer Center|Manisha Shah|National Comprehensive Cancer Network | 2012-11 | Phase 2 |
| NCT01740648 | Recruiting | Recurrent Rectal Cancer|Stage IIA Rectal Cancer|Stage IIB Rectal Cancer|Stage IIC Rectal Cancer|Stage IIIA Rectal Cancer|Stage IIIB Rectal Cancer|Stage IIIC Rectal Cancer | Ohio State University Comprehensive Cancer Center|Evan Wuthrick|National Comprehensive Cancer Network|GlaxoSmithKline | 2012-11 | Phase 1 |
| NCT01750918 | Recruiting | Cancer | GlaxoSmithKline | 2012-12 | Phase 2 |
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 DMSO | |
| Syonnyms | GSK212 |
| Solubility (25°C) * | In vitro | DMSO | 100 mg/mL heating (162 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 Reviews (4)
 Click to enlarge | Rating | |
| 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. |
Product Citations (9)
Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1. [Ohashi K, et al. Proc Natl Acad Sci U S A 2012;109(31):E2127-33]
In vivo MAPK reporting reveals the heterogeneity in tumoral selection of resistance to RAF inhibitors. [Basile KJ, et al. Cancer Res 2013;73(23):7101-10]
Characteristics of lung cancers harboring NRAS mutations. [Ohashi K, et al. Clin Cancer Res 2013;19(9):2584-91]
