Trametinib (GSK1120212)は一種の高度特異性的で、有効なMEK1/2阻害剤で、無細胞試験でIC50値が0.92 nM/1.8 nMですが、c-Raf、B-RafとERK1/2を抑制する活性がありません。
SMYD3 knockout augments the effects of the MEK1/2 inhibitor Trametinib (GSK1120212) in vivo. Representative serial HE staining and IHC for pERK1/2, a marker of Ras activity, and MUC5, a marker of PanIN lesions. All scale bars, 50 um.
Nature 2014 510(7504), 283-7. Trametinib (GSK1120212) purchased from Selleck.
ERK phosphorylates FBW7 at T205. PANC-1 cells were pretreated with the proteasome inhibitor MG132 and trametinib, as indicated, overnight before harvest. Endogenous FBW7 phosphorylation status was examined by immunoblot analysis after immunoprecipitates (IP).
Cell Res 2015 25(5), 561-73. Trametinib (GSK1120212) purchased from Selleck.
MEK2C125S, but not the equivalent MEK1C121S variant, confers robust resistance to dabrafenib and trametinib. Transduced SKMel28 cells were seeded at low density and 24h after seeding were treated with the indicated concentrations of dabrafenib and trametinib every 72-96h. Colonies were stained with crystal violet 10 days post transduction. Photographs are representative of at least two independent transduction experiments.
Nat Commun 2015 5, 5694. Trametinib (GSK1120212) purchased from Selleck.
Ras, MEK and ERK control bronchial epithelial gene expression. Acute versus chronic GSK1120212. Acute (left panels): cells were seeded sparsely and incubated for 4 days in normal media and then subjected to a calcium switch and recovery, in the presence of DMSO (panel 1) or 500 nM GSK1120212 (panel 2). Chronic (right panels): cells were seeded sparsely and incubated for 4 days in DMSO (panel 3) or 500 nM GSK1120212 (panel 4). Cells were subjected to a calcium switch and recovery, in the presence of DMSO (panel 3) or 500 nM GSK1120212 (panel 4). Cells were fixed and stained for ZO-1 and DNA. Scale bar, 20 um.
EMBO Rep 2015 16(1), 87-96. Trametinib (GSK1120212) purchased from Selleck.
Phosphorylation level of ERK1/2 and apoptosis after GSK1120212 exposure. Phosphorylation levels of ERK1/2 after GSK1120212 exposure. When the phosphorylation levels were examined after GSK1120212 exposure (0, 1, 3, 10, and 30 nM), the samples were collected 3 hours after the stimulation. GSK1120212 induced a significant decrease in the phosphorylation levels of ERK1/2 in the hypersensitive cell lines (OCUM-1 and Okajima), compared with that in the non-sensitive cell line (SNU-16). b-actin was used as an internal control.
Mol Cancer Ther 2014 13(12), 3098-106. Trametinib (GSK1120212) purchased from Selleck.
Dose response curve of compound on melanoma cell lines. Compound was dissolved in DMSO, added in a 5-fold dilution series, starting with 5μM, and incubated for 72 hours. Fluorescence was measured after 8 hours incubation in resazurin. Data was normalized to DMSO (maximal viability) and Doxorubicin (minimum viability).
One customer. Trametinib (GSK1120212) purchased from Selleck.
Figure 3 Anti-ErbB3 mAb A4 counteracts the increase of ErbB3-dependent AKT phosphorylation and potentiate growth inhibition
induced by GSK1120212b. (a) LOX IMVI melanoma cells were serum starved and treated with vemurafenib (0.3 μM), with GSK1120212b (GSK, 0.15 μ M) or with their combination in presence or not of anti-ErbB3 mAb A4 (20 μ g/ml) for 24 h. Western blot analysis shows that A4 mAb abrogate ErbB3 phosphotylation as well as the strong increase of pAKT induced by both inhibitors . For densitometric analysis pErbB3/ErbB3, pERK/ERK and pAKT/ATK values are expressed as fold change with respect to the control unstimulated cells to which value = 1 was assigned. Results are expressed as mean values from three independent experiments. (b) Cells were grown in the presence of different doses of GSK combinated or not with A4 mAb (20 μ g/ml) for 10 day. Cells were then dissolved in a Methanol/SDS solution and the adsorbance (595 nm) was read as above. Quantitative analysis for curve fitting and for IC50 evaluation, performed as above, shows that the treatment with A4 enhances the inhibitory effect of GSK on cell growth (IC50 GSK = 115 nM; IC50 GSK + A4 = 19 nM). p-values were calculated and significance level has been defined as above. For IC50 GSK + A4 p < 0,001 vs IC50 GSK. (c) Cells were treated with suboptimal doses of vemurafenib, GSK or their combination in presence or not of A4 mAb (c). The in vitro colony formation assay shows that the addition of A4 significantly inhibits cells growth. *p < 0,01 vs vem-treated or GSK-treated cells; ** p < 0,001 vs vem + GSK- treated cells; NS vs untreated cells.
Trametinib (GSK1120212) purchased from Selleck.
Mouse carcinoma cells were treated with the inhibitors for 16 and 40 h at the concentrations indicated. The effect on S-phase was evident at 16 hrs. (A) whereas apoptosis was induced at 40h. (B) Biological effects of the compounds correlated with effects on phosphorylation of the MEK target ERK. (C) IC50 on S-phase and ERK-posphorylation: TAK-733=1-10nM, GSK1120212=<1nM.
Jonas Nilsson, PhD from University of Gothenburg. Trametinib (GSK1120212) purchased from Selleck.
|製品説明||Trametinib (GSK1120212)は一種の高度特異性的で、有効なMEK1/2阻害剤で、無細胞試験でIC50値が0.92 nM/1.8 nMですが、c-Raf、B-RafとERK1/2を抑制する活性がありません。|
|特性||More potent than PD0325901 or AZD6244.|
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.  GSK1120212 blocks tumor necrosis factor-α and interleukin-6 production from peripheral blood mononuclear cells (PBMCs). 
|In vivo試験||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.  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. |
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.
|体外||DMSO||22 mg/mL (35.74 mM) warming|
|体内||4% DMSO+corn oil||3mg/mL|
* <1 mg/mlは製品が微弱に溶解する或いは溶解しないことを示します。
マス (g) = 濃度 (mol/L) x ボリューム (L) x 分子量 (g/mol)
開始濃度 x 開始体積 = 最終濃度 x 最終体積
この方程式は、一般に略語を使われます：C1V1 = C2V2 ( 輸入 輸出 )
チップス: 化学式は大文字と小文字の区別ができます。C10H16N2O2 c10h16n2o2
|NCT Number||Recruitment||Conditions||Sponsor/Collaborators||Start Date||Phases|
|NCT01723202||Active, not recruiting||Follicular Thyroid Cancer|Insular Thyroid Cancer|Papillary Thyroid Cancer|Recurrent Thyroid Cancer||Manisha Shah|National Comprehensive Cancer Network|Ohio State University Comprehensive Cancer Center||November 7, 2012||Phase 2|
|NCT02672358||Not yet recruiting||Non-Small-Cell Lung Cancer||Novartis Pharmaceuticals|Novartis||October 2017||Phase 2|
|NCT02939846||Withdrawn||Cancer||GlaxoSmithKline||May 2017||Phase 1|
|NCT02447939||Withdrawn||Melanoma||GlaxoSmithKline||May 2017||Phase 1|
|NCT02645149||Not yet recruiting||Melanoma||Melanoma Institute Australia||March 2017||Phase 4|
|NCT02967692||Not yet recruiting||Melanoma||Novartis Pharmaceuticals|Novartis||February 2017||Phase 3|
Could you help us with the best way to prepare Trametinib for in vivo i.p. injections?
S2673 can be dissovled in 4% DMSO/corn oil at 3 mg/ml clearly.
How to solve the problem that this product didn't dissolve up to 10mM in DMSO at room temperature?
The solution can be heated up to 50 degree to help dissolve. Besides, sonication (with a probe sonicator) also helped greatly.