Trametinib (GSK1120212)
别名: JTP-74057 中文名称：曲美替尼
Trametinib (GSK1120212, JTP-74057)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。Trametinib 可激活自噬并诱导凋亡。
Trametinib (GSK1120212) Chemical Structure
CAS: 871700-17-3
产品质控
批次：
纯度：
99.98%
99.98
常与Trametinib (GSK1120212)一起在实验中被使用的化合物
Trametinib和Gefitinib联合有效抑制NRAS/KRAS/BRAF V600野生型结直肠癌(CRC)细胞增殖。
Trametinib和Olaparib在MESO-1/MSTO-211/H2452异种移植物和BE261T PDX模型中显示出明显更高的抗肿瘤效果。
Trametinib与拓扑异构酶2 (Top2)抑制剂Doxorubicin联用对K562细胞的转录组具有拮抗作用。
Trametinib和Dabrafenib联合治疗是FDA批准的用于恶性黑色素瘤和非小细胞肺癌(NSCLC)患者的治疗。
Trametinib和Cisplatin联合治疗在非小细胞肺癌(NSCLC)患者中具有应用潜力。
Trametinib (GSK1120212)相关产品
相关信号通路图
细胞实验数据示例
| 细胞系 | 实验类型 | 给药浓度 | 孵育时间 | 活性描述 | 文献信息 |
|---|---|---|---|---|---|
| Transitional cell carcinoma (TCC) cell lines | Function assay | 25 nM | 6-24 h | Canine TCC cell lines are sensitive to MEK inhibition | 31048548 |
| Human PDAC cell lines (MIA-PACA, PANC-1, CFPAC-1, PL45, CAPAN-2 and HPAF-II) | Function assay | 10 nM or 100 nM | 3-days or 6-days | The concentration of 10 nM trametinib consistently produced significant differences between gefitinib and trametinib alone compared to combination gefitinib and trametinib in all four sensitive cell lines (CFPAC-1, pl45, CAPAN-2 and HPAF-II). No additive effect was observed in the gefitinib insensitive or excitatory cell lines (MIA-Paca and PANC-1) | 30921351 |
| BJAB cells | Function assay | 0.01μM | 24 h | 0.01 μM trametinib effectively suppressed the ERK hyperactivation in BJAB cells caused by the combined treatment of BKM120 and Danusertib. | 30947576 |
| MDA-MB-231, SW480 and SW1116 cells | Function assay | 100 nM | 24 h | trametinib could decrease YAP levels and inhibit LMB-induced YAP upregulation in MDA-MB-231, SW1116 and SW480 cells | 30833665 |
| RG7388-resistant U87MG cells | Function assay | 10 nM | 24 h | Trametinib treatment reduced the invasive phenotype of RG7388 resistant cells. | 30274984 |
| COLO205 | Growth inhibition assay | 72 h | IC50 = 0.001 μM | ChEMBL | |
| HT-29 | Growth inhibition assay | 72 h | IC50 = 0.001 μM | ChEMBL | |
| COLO205 | Growth inhibition assay | 72 h | IC50 = 0.001 μM | ChEMBL | |
| MV522 | Growth inhibition assay | 72 h | IC50 = 0.001 μM | ChEMBL | |
| HT-29 | Growth inhibition assay | 72 h | IC50 = 0.002 μM | ChEMBL | |
| MV522 | Growth inhibition assay | 72 h | IC50 = 0.002 μM | ChEMBL | |
| NCI-H727 | Growth inhibition assay | 72 h | IC50 = 0.002 μM | ChEMBL | |
| NCI-H727 | Growth inhibition assay | 72 h | IC50 = 0.002 μM | ChEMBL | |
| SW1417 | Growth inhibition assay | 72 h | IC50 = 0.003 μM | ChEMBL | |
| SW1417 | Growth inhibition assay | 72 h | IC50 = 0.003 μM | ChEMBL | |
| Calu6 | Growth inhibition assay | 72 h | IC50 = 0.003 μM | ChEMBL | |
| LS1034 | Growth inhibition assay | 72 h | IC50 = 0.004 μM | ChEMBL | |
| SW1463 | Growth inhibition assay | 72 h | IC50 = 0.004 μM | ChEMBL | |
| SW1463 | Growth inhibition assay | 72 h | IC50 = 0.004 μM | ChEMBL | |
| Calu6 | Growth inhibition assay | 72 h | IC50 = 0.004 μM | ChEMBL | |
| LS1034 | Growth inhibition assay | 72 h | IC50 = 0.005 μM | ChEMBL | |
| RKO | Growth inhibition assay | 72 h | IC50 = 0.005 μM | ChEMBL | |
| NCI-H508 | Growth inhibition assay | 72 h | IC50 = 0.008 μM | ChEMBL | |
| KM12 | Growth inhibition assay | 72 h | IC50 = 0.01 μM | ChEMBL | |
| A427 | Growth inhibition assay | 72 h | IC50 = 0.01 μM | ChEMBL | |
| NCI-H1155 | Growth inhibition assay | 72 h | IC50 = 0.01 μM | ChEMBL | |
| HCT8 | Growth inhibition assay | 72 h | IC50 = 0.014 μM | ChEMBL | |
| MDA-MB-175-VII | Growth inhibition assay | 72 h | IC50 = 0.016 μM | ChEMBL | |
| A549 | Growth inhibition assay | 72 h | IC50 = 0.016 μM | ChEMBL | |
| RKO | Growth inhibition assay | 72 h | IC50 = 0.018 μM | ChEMBL | |
| NCI-H23 | Growth inhibition assay | 72 h | IC50 = 0.02 μM | ChEMBL | |
| A427 | Growth inhibition assay | 72 h | IC50 = 0.022 μM | ChEMBL | |
| KM12 | Growth inhibition assay | 72 h | IC50 = 0.023 μM | ChEMBL | |
| NCI-H508 | Growth inhibition assay | 72 h | IC50 = 0.023 μM | ChEMBL | |
| MDA-MB-231 | Growth inhibition assay | 3 days | GI50 = 0.025 μM | ChEMBL | |
| SW837 | Growth inhibition assay | 72 h | IC50 = 0.025 μM | ChEMBL | |
| SW480 | Growth inhibition assay | 72 h | IC50 = 0.026 μM | ChEMBL | |
| NCI-H1355 | Growth inhibition assay | 72 h | IC50 = 0.027 μM | ChEMBL | |
| NCI-H23 | Growth inhibition assay | 72 h | IC50 = 0.029 μM | ChEMBL | |
| EFM19 | Growth inhibition assay | 72 h | IC50 = 0.03 μM | ChEMBL | |
| T84 | Growth inhibition assay | 72 h | IC50 = 0.03 μM | ChEMBL | |
| A549 | Growth inhibition assay | 72 h | IC50 = 0.034 μM | ChEMBL | |
| NCI-H1792 | Growth inhibition assay | 72 h | IC50 = 0.035 μM | ChEMBL | |
| SW480 | Growth inhibition assay | 72 h | IC50 = 0.037 μM | ChEMBL | |
| COR-L23 | Growth inhibition assay | 72 h | IC50 = 0.037 μM | ChEMBL | |
| SW1573 | Growth inhibition assay | 72 h | IC50 = 0.038 μM | ChEMBL | |
| Calu3 | Growth inhibition assay | 72 h | IC50 = 0.039 μM | ChEMBL | |
| HCC827 | Growth inhibition assay | 72 h | IC50 = 0.04 μM | ChEMBL | |
| HOP62 | Growth inhibition assay | 72 h | IC50 = 0.05 μM | ChEMBL | |
| NCI-H1355 | Growth inhibition assay | 72 h | IC50 = 0.052 μM | ChEMBL | |
| NCI-H1792 | Growth inhibition assay | 72 h | IC50 = 0.053 μM | ChEMBL | |
| HCT8 | Growth inhibition assay | 72 h | IC50 = 0.055 μM | ChEMBL | |
| T84 | Growth inhibition assay | 72 h | IC50 = 0.061 μM | ChEMBL | |
| SW900 | Growth inhibition assay | 72 h | IC50 = 0.072 μM | ChEMBL | |
| SW837 | Growth inhibition assay | 72 h | IC50 = 0.074 μM | ChEMBL | |
| DLD1 | Growth inhibition assay | 72 h | IC50 = 0.093 μM | ChEMBL | |
| MDA-MB-175-VII | Growth inhibition assay | 72 h | IC50 = 0.096 μM | ChEMBL | |
| SW900 | Growth inhibition assay | 72 h | IC50 = 0.127 μM | ChEMBL | |
| Calu3 | Growth inhibition assay | 72 h | IC50 = 0.158 μM | ChEMBL | |
| COR-L23 | Growth inhibition assay | 72 h | IC50 = 0.329 μM | ChEMBL | |
| DLD1 | Growth inhibition assay | 72 h | IC50 = 0.632 μM | ChEMBL | |
| 点击查看更多细胞系数据 | |||||
生物活性
| 产品描述 | Trametinib (GSK1120212, JTP-74057)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。Trametinib 可激活自噬并诱导凋亡。 | ||||
|---|---|---|---|---|---|
| 特性 | 药效大于PD0325901或AZD6244 | ||||
| 靶点 |
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| 体外研究(In Vitro) | ||||
| 体外研究活性 | 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] |
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|---|---|---|---|---|
| 激酶实验 | 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 | 细胞系 | HT-29, HCT-15, HCT116, COLO205, LS-174T, SW480, SW620, T84, LoVo和COLO320 | ||
| 浓度 | 溶解在DMSO中至终浓度约10 μM | |||
| 孵育时间 | 3天或4天 | |||
| 方法 | 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。 |
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| 实验图片 | 检测方法 | 检测指标 | 实验图片 | PMID |
| Western blot | ERRα / IDH3 / c-Myc / Cyclin D1 pERK /ERK / pS6 / S6 β-catenin |
|
30185207 | |
| Growth inhibition assay | Cell proliferation MTT assay |
|
30185207 | |
| Immunofluorescence | phospho-PR(S345) β-catenin |
|
29237804 | |
| 体内研究(In Vivo) | ||
| 体内研究活性 | 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] |
|
|---|---|---|
| 动物实验 | Animal Models | 雌雄BALB/c-nu/nu小鼠皮下注射HT-29或COLO205细胞 |
| Dosages | 1 mg/kg/day | |
| Administration | 口服 | |
| NCT Number | Recruitment | Conditions | Sponsor/Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT05275374 | Not yet recruiting | Cancer|BRAF V600 Mutation|Melanoma|Colorectal Cancer|Thyroid Cancer|Nonsmall Cell Lung Cancer |
Xynomic Pharmaceuticals Inc. |
December 2024 | Phase 1|Phase 2 |
| NCT06098872 | Not yet recruiting | Arteriovenous Malformations |
University Health Network Toronto |
November 2023 | Phase 2 |
| NCT05907304 | Recruiting | Advanced or Metastatic Solid Tumors |
Erasca Inc. |
August 17 2023 | Phase 1 |
| NCT05874414 | Recruiting | Cholangiocarcinoma |
Genfit |
August 21 2023 | Phase 1|Phase 2 |
化学信息&溶解度
| 分子量 | 615.39 | 分子式 | C26H23FIN5O4 |
| CAS号 | 871700-17-3 | SDF | Download Trametinib (GSK1120212) SDF |
| 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 | ||
| 储存条件(自收到货起) | |||
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体外溶解度 |
DMSO : 8 mg/mL ( (12.99 mM) ；DMSO吸湿会降低化合物溶解度，请使用新开封DMSO) Water : Insoluble Ethanol : Insoluble |
摩尔浓度计算器 |
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体内溶解度 现配现用，请按从左到右的顺序依次添加，澄清后再加入下一溶剂 |
动物体内配方计算器 | ||||
实验计算
动物体内配方计算器（澄清溶液）
第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量）
mg/kg
g
μL
只
第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系Selleck为您提供正确的澄清溶液配方）
% DMSO
%
% Tween 80
% ddH2O
%DMSO
%
计算结果：
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于μL DMSO溶液（母液浓度mg/mL，注：如该浓度超过该批次药物DMSO溶解度，请先联系Selleck）；
体内配方配制方法：取μL DMSO母液，加入μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入μL ddH2O，混匀澄清。
体内配方配制方法：取μL DMSO母液，加入μL Corn oil，混匀澄清。
注意：1. 首先保证母液是澄清的；
2.一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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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.
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