Trametinib (GSK1120212)
(Synonyms: 曲美替尼; GSK1120212; JTP-74057) 目录号 : GC13508
An inhibitor of MEK1 and MEK2
Cas No.:871700-17-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| 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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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]。
| 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 |
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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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Trametinib (GSK1120212)
The mitogen-activated protein kinase (MEK MAPK/ERK kinase) signaling pathways play a critical role in the regulation of diverse cellular activities, including survival, differentiation, proliferation, motility, and angiogenesis. Therefore, MEK inhibition was recognized as a promising target for antineoplastic therapy. Trametinib (GSK1120212), an oral MEK inhibitor which is selective for MEK1 and MEK2, has been approved by the FDA for the treatment of metastatic melanoma in a combination with a BRAF inhibitor. In this overview, preclinical and clinical data for trametinib are presented including mechanisms based on in vitro studies as well as findings from different clinical studies. The future clinical trial in different solid tumor entities will define the therapeutic role of this targeted therapy approach, possibly as a combination with other targeted therapies such as BRAF inhibitors.
Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial
Background: Low-grade serous carcinoma of the ovary or peritoneum is characterised by MAPK pathway aberrations and its reduced sensitivity to chemotherapy relative to high-grade serous carcinoma. We compared the MEK inhibitor trametinib to physician's choice standard of care in patients with recurrent low-grade serous carcinoma.
Methods: This international, randomised, open-label, multicentre, phase 2/3 trial was done at 84 hospitals in the USA and UK. Eligible patients were aged 18 years or older with recurrent low-grade serous carcinoma and measurable disease, as defined by Response Evaluation Criteria In Solid Tumors version 1.1, had received at least one platinum-based regimen, but not all five standard-of-care drugs, and had received an unlimited number of previous regimens. Patients with serous borderline tumours or tumours containing low-grade serous and high-grade serous carcinoma were excluded. Eligible patients were randomly assigned (1:1) to receive either oral trametinib 2 mg once daily (trametinib group) or one of five standard-of-care treatment options (standard-of-care group): intravenous paclitaxel 80 mg/m2 by body surface area on days 1, 8, and 15 of every 28-day cycle; intravenous pegylated liposomal doxorubicin 40-50 mg/m2 by body surface area once every 4 weeks; intravenous topotecan 4 mg/m2 by body surface area on days 1, 8, and 15 of every 28-day cycle; oral letrozole 2·5 mg once daily; or oral tamoxifen 20 mg twice daily. Randomisation was stratified by geographical region (USA or UK), number of previous regimens (1, 2, or ≥3), performance status (0 or 1), and planned standard-of-care regimen. The primary endpoint was investigator-assessed progression-free survival while receiving randomised therapy, as assessed by imaging at baseline, once every 8 weeks for 15 months, and then once every 3 months thereafter, in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study therapy. This trial is registered with ClinicalTrials.gov, NCT02101788, and is active but not recruiting.
Findings: Between Feb 27, 2014, and April 10, 2018, 260 patients were enrolled and randomly assigned to the trametinib group (n=130) or the standard-of-care group (n=130). At the primary analysis, there were 217 progression-free survival events (101 [78%] in the trametinib group and 116 [89%] in the standard-of-care group). Median progression-free survival in the trametinib group was 13·0 months (95% CI 9·9-15·0) compared with 7·2 months (5·6-9·9) in the standard-of-care group (hazard ratio 0·48 [95% CI 0·36-0·64]; p<0·0001). The most frequent grade 3 or 4 adverse events in the trametinib group were skin rash (17 [13%] of 128), anaemia (16 [13%]), hypertension (15 [12%]), diarrhoea (13 [10%]), nausea (12 [9%]), and fatigue (ten [8%]). The most frequent grade 3 or 4 adverse events in the standard-of-care group were abdominal pain (22 [17%]), nausea (14 [11%]), anaemia (12 [10%]), and vomiting (ten [8%]). There were no treatment-related deaths.
Interpretation: Trametinib represents a new standard-of-care option for patients with recurrent low-grade serous carcinoma.
Funding: NRG Oncology, Cancer Research UK, Target Ovarian Cancer, and Novartis.
Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma
Background: Combination therapy with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved survival in patients with advanced melanoma with BRAF V600 mutations. We sought to determine whether adjuvant dabrafenib plus trametinib would improve outcomes in patients with resected, stage III melanoma with BRAF V600 mutations.
Methods: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 870 patients with completely resected, stage III melanoma with BRAF V600E or V600K mutations to receive oral dabrafenib at a dose of 150 mg twice daily plus trametinib at a dose of 2 mg once daily (combination therapy, 438 patients) or two matched placebo tablets (432 patients) for 12 months. The primary end point was relapse-free survival. Secondary end points included overall survival, distant metastasis-free survival, freedom from relapse, and safety.
Results: At a median follow-up of 2.8 years, the estimated 3-year rate of relapse-free survival was 58% in the combination-therapy group and 39% in the placebo group (hazard ratio for relapse or death, 0.47; 95% confidence interval [CI], 0.39 to 0.58; P<0.001). The 3-year overall survival rate was 86% in the combination-therapy group and 77% in the placebo group (hazard ratio for death, 0.57; 95% CI, 0.42 to 0.79; P=0.0006), but this level of improvement did not cross the prespecified interim analysis boundary of P=0.000019. Rates of distant metastasis-free survival and freedom from relapse were also higher in the combination-therapy group than in the placebo group. The safety profile of dabrafenib plus trametinib was consistent with that observed with the combination in patients with metastatic melanoma.
Conclusions: Adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations than the adjuvant use of placebo and was not associated with new toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov, NCT01682083 ; EudraCT number, 2012-001266-15 .).
Trametinib (GSK1120212) in the treatment of melanoma
Introduction: The discovery of somatic mutations in melanoma has advanced our knowledge of the biology of the disease. The mutations, such as those in NRAS, BRAF, GNAQ and GNA11, promote the growth of melanoma cells in most part through the mitogen-activated protein kinase (MAPK) pathway. Understanding the molecular pathways of some of these mutations has resulted in the successful development of selective BRAF inhibitors. Yet, a cure for advanced melanoma is far from reality. Targeting MAPK/ERK kinase (MEK), an essential intermediary kinase protein within the MAPK pathway, may be a promising way to treat patients with BRAF or other genomic mutation.
Areas covered: The authors discuss the MAPK pathway in melanoma and review the preclinical and clinical studies of the MEK inhibitor, trametinib , in melanoma. They also discuss the potential of using trametinib in the targeted therapy of advanced melanoma.
Expert opinion: Studies have demonstrated the activity of trametinib in BRAF-mutant melanoma, suggesting that it could be a very reasonable alternative to BRAF inhibitors for these patients. Current clinical investigations have shown great promise with the combination of trametinib and dabrafenib in patients with BRAF-mutant melanoma; a number of clinical trials of trametinib in combination with other targeted drugs are underway.
Five-Year Analysis of Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma
Background: In the previously reported primary analysis of this phase 3 trial, 12 months of adjuvant dabrafenib plus trametinib resulted in significantly longer relapse-free survival than placebo in patients with resected stage III melanoma with BRAF V600E or V600K mutations. To confirm the stability of the relapse-free survival benefit, longer-term data were needed.
Methods: We randomly assigned 870 patients who had resected stage III melanoma with BRAF V600E or V600K mutations to receive 12 months of oral dabrafenib (at a dose of 150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. The primary end point was relapse-free survival. Here, we report 5-year results for relapse-free survival and survival without distant metastasis as the site of the first relapse. Overall survival was not analyzed, since the required number of events to trigger the final overall survival analysis had not been reached.
Results: The minimum duration of follow-up was 59 months (median patient follow-up, 60 months for dabrafenib plus trametinib and 58 months for placebo). At 5 years, the percentage of patients who were alive without relapse was 52% (95% confidence interval [CI], 48 to 58) with dabrafenib plus trametinib and 36% (95% CI, 32 to 41) with placebo (hazard ratio for relapse or death, 0.51; 95% CI, 0.42 to 0.61). The percentage of patients who were alive without distant metastasis was 65% (95% CI, 61 to 71) with dabrafenib plus trametinib and 54% (95% CI, 49 to 60) with placebo (hazard ratio for distant metastasis or death, 0.55; 95% CI, 0.44 to 0.70). No clinically meaningful between-group difference in the incidence or severity of serious adverse events was reported during the follow-up period.
Conclusions: In the 5-year follow-up of a phase 3 trial involving patients who had resected stage III melanoma with BRAF V600E or V600K mutations, 12 months of adjuvant therapy with dabrafenib plus trametinib resulted in a longer duration of survival without relapse or distant metastasis than placebo with no apparent long-term toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov number, NCT01682083; EudraCT number, 2012-001266-15.).