Trametinib (GSK1120212)

目录号:S2673 别名: JTP-74057

Trametinib (GSK1120212) Chemical Structure

Molecular Weight(MW): 615.39

Trametinib (GSK1120212)是一种高特异性的,有效的MEK1/2抑制剂,无细胞试验中IC50为0.92 nM/1.8 nM,对c-Raf, B-Raf, ERK1/2没有抑制活性。

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客户购买Selleck的此次产品后发表的文献49篇:

客户使用该产品的10个实验数据:

  • 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.

    Immunofluorescence of E-cadherin, vimentin and DAPI in cells from grown on chamber slides and treated with 100 nM GSK1120212/trametinib. Scale bars represent 50 um.

    Cancer Discov 2014 4(2), 232-45. 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.

    RDEA119 (1 uM) or JTP-74057 (0.1 uM) abolished the effects of G1 on DAPK1 and NR2B phosphorylation. The data were pooled from five independent experiments.

    J Neurosci 2012 32, 4887-900. 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.

产品安全说明书

MEK抑制剂选择性比较

生物活性

产品描述 Trametinib (GSK1120212)是一种高特异性的,有效的MEK1/2抑制剂,无细胞试验中IC50为0.92 nM/1.8 nM,对c-Raf, B-Raf, ERK1/2没有抑制活性。
特性 药效大于PD0325901或AZD6244
靶点
MEK1 [1]
(Cell-free assay)
MEK2 [1]
(Cell-free assay)
0.92 nM 1.8 nM
体外研究

GSK1120212抑制 MBP 的磷酸化,对于不同亚型的Raf和MEK 而言,IC50在0.92 nM-3.4 nM。GSK1120212对c-Raf, B-Raf, ERK1和ERK2的激酶活性没有抑制作用。另外,GSK1120212对于其它98种激酶没有很强的抑制作用。GSK1120212对于人结肠癌细胞系有很强的抑制作用,其中HT-29和COLO205细胞组成型表达有活性的B-Raf突变,这两种细胞对GSK1120212最为敏感,IC50分别是0.48 nM 和 0.52 nM。含有k-Raf突变的细胞系对GSK1120212的敏感性介于如下范围,IC50是2.2-174 nM. 相反地,COLO320 DM细胞中B-Raf 和K-Ras均为野生型,因而即便在10 μM都对GSK1120212有抗性。用GSK1120212处理24小时可以诱导所有敏感细胞的细胞周期停滞在G1期。与此一致,GSK1120212处理使得大部分人结肠癌细胞系中p15INK4b 和/或p27KIP1的表达量上升。GSK1120212能诱导HT-29和COLO205细胞的凋亡,COLO205细胞更为敏感。[1] GSK1120212抑制外周血单核细胞产生肿瘤坏死因子-α和白介素-6。 [2]

体内研究 按0.3 mg/kg或1 mg/kg 的剂量口服GSK1120212(一天一次共14天)能有效抑制HT-29肿瘤,1 mg/kg 的剂量可完全抑制肿瘤生长。在癌症组织中,一次口服1 mg/kg GSK1120212能完全抑制ERK1/2的磷酸化,14天后能提高p15INK4b和p27KIP1的表达量。在COLO205肿瘤模型中,0.3 mg/kg剂量的GSK1120212就足以抑制肿瘤生长,1 mg/kg剂量的GSK1120212可以使2/3的老鼠的肿瘤消退至可检测水平之下。[1] 0.1 mg/kg剂量的GSK1120212完全抑制佐剂性关节炎(AIA)和II型胶原诱导的关节炎(CIA) Lewis大鼠或DBA1/J小鼠。[2]

推荐的实验操作(此推荐来自于公开的文献所以Selleck并不保证其有效性)

激酶实验:[1]
+ 展开

Raf-MEK-ERK级联激酶检测:

非磷酸化的髓鞘碱性蛋白(MBP)涂覆到ELISA板上,B-Raf/c-Raf的活性形式与非磷酸化MEK1/MEK2和ERERK2混合在10 μM ATP和12.5 mM MgCl2,其MOPS缓冲液中含有不同浓度的GSK1120212。 MBP的磷酸化是由抗磷酸化的MBP抗体进行检测。
细胞实验:[1]
+ 展开
  • Cell lines: HT-29, HCT-15, HCT116, COLO205, LS-174T, SW480, SW620, T84, LoVo和COLO320
  • Concentrations: 溶解在DMSO中至终浓度约10 μM
  • Incubation Time: 3天或4天
  • Method: 指数生长的细胞预培养在96孔组织培养板中24小时后用GSK1120212孵育。细胞生长是通过体外毒理学测定试剂盒(基于磺酰罗丹明B)检测。对于细胞凋亡测定,漂浮和贴壁细胞被收集并用70%乙醇固定。用PBS洗涤后,将细重胞悬在100微克/毫升RNA酶和25微克/毫升的碘化丙啶(PI)中,至于37℃黑暗中30分钟。每一个单细胞的DNA含量是用流式细胞仪Cytomics FC500或番石榴EasyCyte来确定。
    (Only for Reference)
动物实验:[1]
+ 展开
  • Animal Models: 雌雄BALB/c-nu/nu小鼠皮下注射HT-29或COLO205细胞
  • Formulation: 溶解于10%的Cremophor EL-10%PEG400
  • Dosages: 1 mg/kg/day
  • Administration: 口服
    (Only for Reference)

溶解度 (25°C)

体外 DMSO 22 mg/mL warmed (35.74 mM)
Water Insoluble
Ethanol Insoluble
体内 从左到右依次加入纯溶剂:
4% DMSO+corn oil
3mg/mL

* 溶解度检测是由Selleck技术部门检测的,可能会和文献中提供的溶解度有所差异,这是由于生产工艺和批次不同产生的正常现象。请按照顺序依次加入各个纯溶剂。

化学数据

分子量 615.39
化学式

C26H23FIN5O4

CAS号 871700-17-3
稳定性 powder
别名 JTP-74057

计算器

摩尔浓度计算器

摩尔浓度计算器

本计算器可帮助您计算出特定溶液中溶质的质量、溶液浓度和体积之间的关系,公式为:

质量 (g) = 浓度 (mol/L) x 体积 (L) x 分子量 (g/mol)

摩尔浓度计算公式

  • 质量
    浓度
    体积
    分子量

*在配置溶液时,请务必参考Selleck产品标签上、MSDS / COA(可在Selleck的产品页面获得)批次特异的分子量使用本工具。

稀释计算器

稀释计算器

用本工具协助配置特定浓度的溶液,使用的计算公式为:

开始浓度 x 开始体积 = 最终浓度 x 最终体积

稀释公式

稀释公式一般简略地表示为: C1V1 = C2V2 ( 输入 输出 )

  • C1
    V1
    C2
    V2

在配置溶液时,请务必参考Selleck产品标签上、MSDS / COA(可在Selleck的产品页面获得)批次特异的分子量使用本工具。.

连续稀释计算器方程

  • 连续稀释

  • 计算结果

  • C1=C0/X C1: LOG(C1):
    C2=C1/X C2: LOG(C2):
    C3=C2/X C3: LOG(C3):
    C4=C3/X C4: LOG(C4):
    C5=C4/X C5: LOG(C5):
    C6=C5/X C6: LOG(C6):
    C7=C6/X C7: LOG(C7):
    C8=C7/X C8: LOG(C8):
分子量计算器

分子量计算器

通过输入化合物的化学式来计算其分子量:

总分子量:g/mol

注:化学分子式大小写敏感。C10H16N2O2 c10h16n2o2

摩尔浓度计算器

质量 浓度 体积 分子量
计算

临床试验信息

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

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操作手册

如果有其他问题,请给我们留言。

  • * 必填项

常见问题及建议解决方法

  • 问题 1:

    Could you help us with the best way to prepare Trametinib for in vivo i.p. injections?

  • 回答:

    S2673 can be dissovled in 4% DMSO/corn oil at 3 mg/ml clearly.

  • 问题 2:

    How to solve the problem that this product didn't dissolve up to 10mM in DMSO at room temperature?

  • 回答:

    The solution can be heated up to 50 degree to help dissolve. Besides, sonication (with a probe sonicator) also helped greatly.

MEK Signaling Pathway Map

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID