Trametinib (GSK1120212)
(Synonyms: 曲美替尼; GSK1120212; JTP-74057) 目录号 : GC13508
Trametinib (GSK1120212, JTP-74057) 是第二代 MEK 激酶小分子抑制剂。
Cas No.:871700-17-3
Sample solution is provided at 25 µL, 10mM.
Trametinib (GSK1120212, JTP-74057) is a second-generation small molecule inhibitor of MEK kinase. It functions as allosteric, ATP noncompetitive inhibitor with nanomolar activity against both MEK 1 and MEK 2 kinases with IC50 is 0.7-14.9 nM for MEK1/MEK2[3,7].
Trametinib (GSK1120212), identified as a potent p15INKb inducer, modulates p27KIP1, cyclin D1, cyclin A and c-Myc protein levels and induces G1 arrest in HT-29 cells[2]. Trametinib (GSK1120212) blocked tumor necrosis factor-α and interleukin-6 production from PBMCs. AIA and CIA development were suppressed almost completely by 0.1 mg/kg of JTP-74057 or 10 mg/kg of leflunomide. In the CIA, Trametinib (GSK1120212), but not leflunomide, suppressed collagen-reactive T-cell proliferation ex vivo[1]. Among the different cell lines evaluated in the study, those with either BRAFV600E mutation or activating mutations in KRAS or NRAS were the most sensitive.Trametinib (GSK1120212) inhibited the MEK1/2-dependent activating dual phosphorylation of ERK1/2 on both T202 and Y204[4].
In xenograft models of HT-29 and COLO205 colorectal tumor cell lines, trametinib demonstrated robust anticancer activity when administered daily for 14 days, Tumor growth was significantly suppressed in mice treated with 100 mg/kg Trametinib (GSK1120212) during the course of the treatment, by single oral dosing of 100 mg/kg Trametinib (GSK1120212), the phosphorylation of ERK1/2 in the established tumor tissues was completely inhibited, and both p15INK4b and p27KIP1 mRNA levels were upregulated in parallel[2,5]. In patients treated with Trametinib (GSK1120212)for malignant melanoma most common adverse events observed were rash, diarrhea, peripheral edema, fatigue, and dermatitis acneiform[6].
References:
[1]. Yamaguchi T, Kakefuda R, 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 May;61(5):445-54. doi: 10.1007/s00011-011-0431-5. Epub 2012 Jan 14. PMID: 22245957.
[2]. Yamaguchi T, Yoshida T, et,al. Identification of JTP-70902, a p15(INK4b)-inductive compound, as a novel MEK1/2 inhibitor. Cancer Sci. 2007 Nov;98(11):1809-16. doi: 10.1111/j.1349-7006.2007.00604.x. Epub 2007 Sep 2. PMID: 17784872.
[3]. be H, Kikuchi S, Hayakawa K, 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. doi: 10.1021/ml200004g. PMID: 24900312; PMCID: PMC4018163.
[4]. Gilmartin AG, Bleam MR, et,al. GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition. Clin Cancer Res. 2011 Mar 1;17(5):989-1000. doi: 10.1158/1078-0432.CCR-10-2200. Epub 2011 Jan 18. Erratum in: Clin Cancer Res. 2012 Apr 15;18(8):2413. PMID: 21245089.
[5]. Gilmartin AG, Bleam MR, et,al. GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition. Clin Cancer Res. 2011 Mar 1;17(5):989-1000. doi: 10.1158/1078-0432.CCR-10-2200. Epub 2011 Jan 18. Erratum in: Clin Cancer Res. 2012 Apr 15;18(8):2413. PMID: 21245089.
[6]. Flaherty KT, Infante JR, et,al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012 Nov 1;367(18):1694-703. doi: 10.1056/NEJMoa1210093. Epub 2012 Sep 29. PMID: 23020132; PMCID: PMC3549295.
[7]. Zeiser R, Andrlová H, et,al. Trametinib (GSK1120212). Recent Results Cancer Res. 2018;211:91-100. doi: 10.1007/978-3-319-91442-8_7. PMID: 30069762.
Trametinib (GSK1120212, JTP-74057) 是第二代 MEK 激酶小分子抑制剂。它作为变构的 ATP 非竞争性抑制剂，对 MEK 1 和 MEK 2 激酶具有纳摩尔活性，对 MEK1/MEK2 的 IC50 为 0.7-14.9 nM[3,7]。
Trametinib (GSK1120212) 被确定为一种有效的 p15INKb 诱导剂，可调节 p27KIP1、细胞周期蛋白 D1、细胞周期蛋白 A 和 c-Myc 蛋白水平，并诱导 HT-29 细胞发生 G1 期阻滞[2]。曲美替尼 (GSK1120212) 可阻断 PBMC 中肿瘤坏死因子-α 和白细胞介素 6 的产生。 AIA 和 CIA 的发展几乎完全被 0.1 mg/kg 的 JTP-74057 或 10 mg/kg 的来氟米特抑制。在 CIA 中，Trametinib (GSK1120212)，而不是来氟米特，在体外抑制胶原反应性 T 细胞增殖[1]。在研究中评估的不同细胞系中，具有 BRAFV600E 突变或 KRAS 或 NRAS 激活突变的细胞系最敏感。Trametinib (GSK1120212) 抑制 T202 和 Y204 上 ERK1/2 的 MEK1/2 依赖性激活双重磷酸化[4].
在 HT-29 和 COLO205 结直肠肿瘤细胞系的异种移植模型中，trametinib 在连续 14 天每天给药时表现出强大的抗癌活性，在接受 100 mg/kg Trametinib (GSK1120212) 处理的小鼠中，肿瘤生长在通过单次口服 100 mg/kg Trametinib (GSK1120212) 治疗，已建立的肿瘤组织中 ERK1/2 的磷酸化被完全抑制，p15INK4b 和 p27KIP1 mRNA 水平同时上调[2,5 ]。在使用曲美替尼 (GSK1120212) 治疗恶性黑色素瘤的患者中，观察到的最常见不良事件是皮疹、腹泻、外周水肿、疲劳和痤疮样皮炎[6]。
| Kinase experiment [1]: | |
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Preparation Method |
Two micrograms of dephosphorylated MBP (Upstate) in 0.2 M sodium carbonate (pH 9.4) was coated onto 96-well plates at 4 ¡ムovernight. After blocking with 1% BSA, the inactive forms of MEK1 (2 ng) or MEK2 (4 ng) with inactive ERK2 (50 ng) diluted in assay buffer were preincubated in the plates with test compounds£¨including Trametinib (GSK1120212)£©at room temperature for 10 min. The kinase reaction was started by the addition of active B-Raf (V599E) or c-Raf, with 10 M ATP and 12.5 mM MgCl2. After incubation at 30 C for 30 min, the phosphorylation of MBP by ERK2 was detected with peroxidase-labeled antiphosphorylated MBP antibody. |
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Reaction Conditions |
Trametinib (GSK1120212) with protein at room temperature for 10 minutes |
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Applications |
Trametinib (GSK1120212) binds specifically to MEK1/2.IC50 in cell-free assay was 0.92 nM/1.8 nM. |
| Cell experiment [1]: | |
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Cell lines |
HT-29 cells |
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Preparation Method |
Cells were precultured for 24 h and then exposed to JTP-70902. After incubation with Trametinib (GSK1120212) for 4 days, cell viability was assessed using Cell Counting Kit-8. |
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Reaction Conditions |
0-1000nM Trametinib (GSK1120212) for 4 days |
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Applications |
Trametinib (GSK1120212), identified as a potent p15INKb inducer, modulates p27KIP1, cyclin D1, cyclin A and c-Myc protein levels and induces G1 arrest in HT-29 cells. |
| Animal experiment [1]: | |
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Animal models |
Trametinib (GSK1120212) in the nude mouse HT-29 xenograft model |
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Preparation Method |
HT-29 cells were inoculated subcutaneously into the right flank of nude mice, and Trametinib (GSK1120212) was administered orally twice daily for 21 days starting from 5 days after the inoculation. |
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Dosage form |
10-100mg/kg Trametinib (GSK1120212) twice daily for 21 days |
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Applications |
Tumor growth was significantly suppressed in mice treated with 100 mg/kg Trametinib (GSK1120212) during the course of the treatment. |
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References: [1]. Yamaguchi T, Yoshida T,et,al. Identification of JTP-70902, a p15(INK4b)-inductive compound, as a novel MEK1/2 inhibitor. Cancer Sci. 2007 Nov;98(11):1809-16. doi: 10.1111/j.1349-7006.2007.00604.x. Epub 2007 Sep 2. PMID: 17784872. |
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| Cas No. | 871700-17-3 | SDF | |
| 别名 | 曲美替尼; GSK1120212; JTP-74057 | ||
| 化学名 | N-[3-[3-cyclopropyl-5-(2-fluoro-4-iodoanilino)-6,8-dimethyl-2,4,7-trioxopyrido[4,3-d]pyrimidin-1-yl]phenyl]acetamide | ||
| Canonical 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 | ||
| 分子式 | C26H23FIN5O4 | 分子量 | 615.39 |
| 溶解度 | ≥ 15.38mg/mL in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.625 mL | 8.1249 mL | 16.2499 mL |
| 5 mM | 0.325 mL | 1.625 mL | 3.25 mL |
| 10 mM | 0.1625 mL | 0.8125 mL | 1.625 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 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GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
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，
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 saline，混匀澄清。
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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Quality Control & SDS
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- Purity: >99.00%
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