Trametinib (GSK1120212)
Trametinib (also known as GSK1120212 or JTP 74057), originally identified as a p15 inductive compound, is a novel and potent allosteric inhibitor of MEK kinase, which exhibits ATP non-competitive inhibition against MEK1 and MEK2 kinase. It has demonstrated broad antitumor activities in a variety of tumor xgenograft models, including HT-29 and COLO205 colorectal tumor cell lines. Trametinib induces expression of p15 and p27, reduces cyclin D1 levels, and causes dephosphorylation of RB protein and G1-phase arrest with a reduction of TS expression in HT-29 cells. It also effectively inhibits p-ERK 1/2 resulting in cell growth inhibition in tumor cell lines harboring B-RAF mutant.
Reference
Akintunde Akinleye, Muhammad Furqan, Nikhil Mukhi, Pavan Ravella and Delong Liu. MEK and the inhibitors: from bench to bedside. Journal of Hematology & Oncology 2013, 6:27
Motoki Watanabe, Yoshihiro Sowa, Mayumi Yogosawa and Toshiyuki Sakai. Novel MEK inhibitor trametinib and other retinoblastoma gene (RB)-reactivating agents enhance efficacy of 5-fluorouracil on human colon cancer cells. Cancer Sci 2013; 104(6): 687-693
- 1. Cho SY, Chae J, et al. "Unstable Genome and Transcriptome Dynamics during Tumor Metastasis Contribute to Therapeutic Heterogeneity in Colorectal Cancers." Clin Cancer Res. 2019 Jan 22. PMID:30670495
- 2. Buhl JL, Selt F, et al. "The senescence-associated secretory phenotype mediates oncogene-induced senescence in pediatric pilocytic astrocytoma." Clin Cancer Res. 2018 Dec 7. pii: clincanres.1965.2018. PMID:30530705
- 3. Knickelbein K, Tong J, et al."Restoring PUMA induction overcomes KRAS-mediated resistance to anti-EGFR antibodies in colorectal cancer." Oncogene. 2018 May 14. PMID:29755130
- 4. Wang YN, Lee HH, et al. "Angiogenin/Ribonuclease 5 Is an EGFR Ligand and a Serum Biomarker for Erlotinib Sensitivity in Pancreatic Cancer." Cancer Cell. 2018 Apr 9;33(4):752-769.e8. PMID:29606349
- 5. Sieber J, Wieder N, et al. "GDC-0879, a BRAF(V600E) Inhibitor, Protects Kidney Podocytes from Death." Cell Chem Biol. 2017 Dec 6. PMID:29249695
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| Physical Appearance | A solid |
| Storage | Store at -20°C |
| M.Wt | 615.39 |
| Cas No. | 871700-17-3 |
| Formula | C26H23FIN5O4 |
| Synonyms | Trametinib, GSK-1120212, GSK1120212, Mekinist, JTP74057, JTP-74057 |
| Solubility | ≥15.38mg/mL in DMSO |
| Chemical Name | N-[3-[3-cyclopropyl-5-(2-fluoro-4-iodoanilino)-6,8-dimethyl-2,4,7-trioxopyrido[4,3-d]pyrimidin-1-yl]phenyl]acetamide |
| SDF | Download SDF |
| 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 |
| Shipping Condition | Evaluation sample solution : ship with blue ice.All other available size: ship with RT , or blue ice upon request |
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. |
| Cell experiment: [1] | |
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Cell lines |
HT-29 cells |
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Preparation method |
The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months. |
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Reaction Conditions |
100 nM, 72 hours |
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Applications |
Trametinib showed a subnanomolar IC50 value for 72 h in a Cell Counting Kit-8 assay of human colon cancer HT-29 cells. The treatment with trametinib for 24 h dose-dependently increased the G1 phase with a decrease in the S phase, and 72 h treatment induced apoptosis in a dose-dependent manner together with G1 arrest. |
| Animal experiment: [2] | |
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Animal models |
Male ICR mice |
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Dosage form |
Oral administration, 3 mg/kg, daily |
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Applications |
GSK1120212 was effective at blocking phosphorylation of ERK over 24 h and 7 d. To test whether the inhibitor blocked adaptive growth, mice were treated with GSK1120212 and/or the trypsin inhibitor camostat mesylate S (TI) for 7 d. TI-induced pancreatic growth was blocked by GSK1120212 as measured by pancreatic mass, protein, DNA, and RNA content. These results show that GSK1120212 like PD0325901 blocks pancreatic adaptive growth induced by TI. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1] Watanabe M, Sowa Y, Yogosawa M, et al. Novel MEK inhibitor trametinib and other retinoblastoma gene (RB)-reactivating agents enhance efficacy of 5‐fluorouracil on human colon cancer cells. Cancer science, 2013, 104(6): 687-693. [2] Holtz B J, Lodewyk K B, Sebolt-Leopold J S, et al. ERK Activation is Required for CCK-mediated Pancreatic Adaptive Growth in Mice. American Journal of Physiology-Gastrointestinal and Liver Physiology, 2014: ajpgi. 00163.2014. | |
| Description | Trametinib (GSK1120212) is a highly specific and potent inhibitor of MEK1/2 with IC50 of 0.92 nM/1.8 nM. | |||||
| Targets | MEK1 | MEK2 | ||||
| IC50 | 0.92 nM | 1.8 nM | ||||
Quality Control & MSDS
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Abstract
GSK1120212, an inhibitor of MEK1 and MEK2, is sensitive to various cell lines including RAF/RAS mutant solid tumor cell lines, breast cancer cell lines, acute myeloid leukemia cell lines and chronic myeloid leukemia cell lines and is less sensitive to cell lines with an expression pattern suggestive of epithelial-to-mesenchymal transition, where expression of gene DUSP6 was associated with GSK1120212 sensitivity.
Abstract
The enzymatic, cellular and in vivo activities of GSK1120212, a MEK1/2 inhibitor with promising antitumor activity, have been characterized.
Abstract
Somatic mutations involved in MAPK pathway, including NRAS, BRAF, GNAQ and GNA11, are associated with melanoma. Targeting MEK has the potential to be incorporated into the treatment of melanoma patients with those mutations.
Abstract
GSK1120212 is an inhibitor of MEK1/2 that exhibits antitumor activity against colorectal cancer cells through growth inhibition and induced apoptosis. Addition of an Akt inhibitor or a few standard-of-care agents could enhance the antitumor activity of GSK1120212.