A3018-500mg | Trametinib (GSK1120212) [871700-17-3] Clinisciences

Background

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

Product Citation

1. Junli Wang, Sijia Weng, et al. "PKCι induces differential phosphorylation of STAT3 to modify STAT3-related signaling pathways in pancreatic cancer cells." J Cell Commun Signal. 2023 Aug 7. PMID: 37548811
2. Paul J Myers, Sung Hyun Lee, et al. "An integrated mechanistic and data-driven computational model predicts cell responses to high-and low-affinity EGFR ligands." bioRxiv. 2023 Jun 26:2023.06.25.543329. PMID: 37425852
3. Xiaofei Zhang, Tiebo Mao, et al. "Synergistic blocking of RAS downstream signaling and epigenetic pathway in KRAS mutant pancreatic cancer." Aging (Albany NY). 2022 Apr 25;14(8):3597-3606. PMID: 35468095
4. Wendy S. Chen, Yan Liang, et al. "Single-cell transcriptomics reveals opposing roles of Shp2 in Myc-driven liver tumor cells and microenvironment." Cell Rep. 2021 Nov 9;37(6):109974. PMID: 34758313
5. Heng-Huan Lee, Ying-Nai Wang, et al. "Human ribonuclease 1 serves as a secretory ligand of ephrin A4 receptor and induces breast tumor initiation." Nat Commun. 2021 May 13;12(1):2788. PMID: 33986289
6. Gabriele Manzella, Leonie D. Schreck, et al. "Phenotypic profiling with a living biobank of primary rhabdomyosarcoma unravels disease heterogeneity and AKT sensitivity." Nature Communications volume 11, Article number: 4629 (2020). PMID: 32934208
7. Xu WF, Wang ZJ, et al. "Huai Qi Huang-induced Apoptosis via Down-regulating PRKCH and Inhibiting RAF/MEK/ERK Pathway in Ph+ Leukemia Cells." Curr Med Sci. 2020;40(2):354-362. PMID: 32337697
8. Ruibin Bai, Yajie Zhang, et al. "Isolation, characterization and immunomodulatory activity of oligosaccharides from Codonopsis pilosula." Journal of Functional Foods. Volume 72, September 2020, 104070
9. Day EK, Sosale NG, et al. "Glioblastoma Cell Resistance to EGFR and MET Inhibition Can Be Overcome via Blockade of FGFR-SPRY2 Bypass Signaling." Cell Rep. 2020;30(10):3383-3396.e7. PMID: 32160544
10. Park SM, Hwang CY, et al. "Feedback analysis identifies a combination target for overcoming adaptive resistance to targeted cancer therapy." Oncogene. 2020;39(19):3803-3820. PMID: 32157217
11. Challa S, Husain K, et al. "Targeting the IκB Kinase Enhancer and Its Feedback Circuit in Pancreatic Cancer." Transl Oncol. 2020;13(2):481–489. PMID: 32004866
12. Satoh TK, Mellett M, et al. "IL-36γ drives skin toxicity induced by EGFR/MEK inhibition and commensal Cutibacterium acnes." J Clin Invest. 2019 Dec 5. pii: 128678. PMID: 31805013
13. Roche SL, Kutsyr O, et al. "Norgestrel, a Progesterone Analogue, Promotes Significant Long-Term Neuroprotection of Cone Photoreceptors in a Mouse Model of Retinal Disease." Invest Ophthalmol Vis Sci. 2019 Jul 1;60(8):3221-3235. PMID: 31335948
14. Juliane Buhl. "The senescence-associated secretory phenotype regulates the growth behavior of pediatric pilocytic astrocytoma." Ruperto Carola University Heidelberg. 2018.
15. 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
16. 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
17. 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
18. 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
19. 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
20. Hogstad B, Berres ML, et al. "RAF/MEK/extracellular signal-related kinase pathway suppresses dendritic cell migration and traps dendritic cells in Langerhans cell histiocytosis lesions." J Exp Med. 2018 Jan 2;215(1):319-336. PMID: 29263218
21. Yong LK, Lai S, et al. "Overexpression of Semaphorin-3E enhances pancreatic cancer cell growth and associates with poor patient survival." Oncotarget. 2016 Dec 27;7(52):87431-87448. PMID: 27911862

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Chemical Properties

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	insoluble in H2O; insoluble in EtOH; ≥15.38 mg/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	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Protocol

Cell experiment: [1]
Cell lines	HT-29 cells
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.
Reaction Conditions	100 nM, 72 hours
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]
Animal models	Male ICR mice
Dosage form	Oral administration, 3 mg/kg, daily
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.
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.
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.