Trametinib
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MedKoo CAT#: 201458

CAS#: 871700-17-3

Description: Trametinib, also known as GSK1120212, is a n orally bioavailable inhibitor of mitogen-activated protein kinase kinase (MEK MAPK/ERK kinase) with potential antineoplastic activity. Trametinib specifically binds to and inhibits MEK 1 and 2, resulting in an inhibition of growth factor-mediated cell signaling and cellular proliferation in various cancers. MEK 1 and 2, dual specificity threonine/tyrosine kinases often upregulated in various cancer cell types, play a key role in the activation of the RAS/RAF/MEK/ERK signaling pathway that regulates cell growth. On May 29, 2013, FDA approved T rametinib.


Chemical Structure

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Trametinib
CAS# 871700-17-3

Theoretical Analysis

MedKoo Cat#: 201458
Name: Trametinib
CAS#: 871700-17-3
Chemical Formula: C26H23FIN5O4
Exact Mass: 615.07788
Molecular Weight: 615.39
Elemental Analysis: C, 50.74; H, 3.77; F, 3.09; I, 20.62; N, 11.38; O, 10.40

Price and Availability

Size Price Availability Quantity
200.0mg USD 150.0 Ready to ship
500.0mg USD 350.0 Ready to ship
1.0g USD 650.0 Ready to ship
2.0g USD 950.0 Ready to ship
5.0g USD 1950.0 Ready to ship
10.0g USD 2950.0 Ready to ship
20.0g USD 4650.0 Ready to ship
100.0g USD 7950.0 2 Weeks
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Synonym: GSK 1120212 GSK1120212; GSK-1120212; JTP74057; Trametinib. Brand name: Mekinist.

IUPAC/Chemical Name: N-[3-[3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-3,4,6,7-tetrahydro-6,8-dimethyl-2,4,7-trioxopyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl]acetamide

InChi Key: LIRYPHYGHXZJBZ-UHFFFAOYSA-N

InChi Code: InChI=1S/C26H23FIN5O4/c1-13-22-21(23(31(3)24(13)35)30-20-10-7-15(28)11-19(20)27)25(36)33(17-8-9-17)26(37)32(22)18-6-4-5-16(12-18)29-14(2)34/h4-7,10-12,17,30H,8-9H2,1-3H3,(H,29,34)

SMILES Code: CC(NC1=CC=CC(N(C(C(C(N2C3CC3)=O)=C(NC4=CC=C(I)C=C4F)N5C)=C(C)C5=O)C2=O)=C1)=O

Appearance: white solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Trametinib (GSK1120212; JTP-74057) is an MEK inhibitor that inhibits MEK1 and MEK2 with IC50s of about 2 nM.
In vitro activity: Interestingly, several IAV (Influenza A virus)-induced cytokines were reduced on mRNA level in presence of Trametinib (Fig. 4A and B). The expression of IFNβ and the interferon stimulated gene (ISG) MxA was only found to be reduced by Trametinib in infected cells (Fig. 4A), but not strongly affected in vRNA-transfected cells (Fig. 4C). The results indicate that the cellular IFN response is not directly limited by Trametinib. Rather it seems to be primarily indirectly affected by reduced viral replication than being directly caused by deregulation of the Raf/MEK/ERK signaling cascade. Indeed, expression of IFNβ and MxA are not yet described to be directly regulated by the Raf/MEK/ERK signaling cascade. Considering Trametinib as antiviral drug it is beneficial that Trametinib does not directly alter the IFN response which is an important arm of cellular antiviral defense. A clearly decreased induction by Trametinib was also detectable for IL6, CCL5 and CXCL10 mRNA expression, which were induced by infection with PR8M/H1N1 (Fig. 4B). Reference: Mol Cancer Ther. 2016 Jan;15(1):172-83. https://pubmed.ncbi.nlm.nih.gov/29990517/
In vivo activity: This study examined the mechanism by which trametinib impacts T-cell subpopulations after islet transplantation. T-cell subpopulations isolated from the liver and spleen of recipient mice on day 7, which were treated with vehicle or with 0.1 or 0.3 mg/kg trametinib, were analyzed by flow cytometry (n = 3/group). The ratio of CD8+ T cells to CD4+ T cells in the liver of trametinib-treated mice tended to be lower than that in the vehicle-treated group (Figure 4A; 1-way ANOVA; P = 0.26), indicating that trametinib suppresses infiltration of the liver by CD8+ T cells. Among the different CD4+ T-cell subpopulations, trametinib increased the percentage of naive T cells (CD62L+CD44–) in the liver in a dose-dependent manner; it also reduced the percentage of effector memory T cells (CD62L-CD44+) in the liver and spleen (Figure 4B; 1-way ANOVA; all P < 0.05). By contrast, trametinib had no effect on CD8+ T-cell subpopulations in the liver or spleen (Figure 4C). These results suggest that (at least in vivo) trametinib mainly suppresses functional differentiation of CD4+ naive T cells. Reference: Transplant Direct. 2020 Sep; 6(9): e591. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423917/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 27.67 44.96

Preparing Stock Solutions

The following data is based on the product molecular weight 615.39 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Itamura H, Shindo T, Tawara I, Kubota Y, Kariya R, Okada S, Komanduri KV, Kimura S. The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effects. JCI Insight. 2016 Jul 7;1(10):e86331. doi: 10.1172/jci.insight.86331. PMID: 27699218; PMCID: PMC5033881. 2. Bridgeman VL, Wan E, Foo S, Nathan MR, Welti JC, Frentzas S, Vermeulen PB, Preece N, Springer CJ, Powles T, Nathan PD, Larkin J, Gore M, Vasudev NS, Reynolds AR. Preclinical Evidence That Trametinib Enhances the Response to Antiangiogenic Tyrosine Kinase Inhibitors in Renal Cell Carcinoma. Mol Cancer Ther. 2016 Jan;15(1):172-83. doi: 10.1158/1535-7163.MCT-15-0170. Epub 2015 Oct 20. PMID: 26487278. 3. Tada S, Anazawa T, Shindo T, Yamane K, Inoguchi K, Fujimoto N, Nagai K, Masui T, Okajima H, Takaori K, Sumi S, Uemoto S. The MEK Inhibitor Trametinib Suppresses Major Histocompatibility Antigen-mismatched Rejection Following Pancreatic Islet Transplantation. Transplant Direct. 2020 Aug 12;6(9):e591. doi: 10.1097/TXD.0000000000001045. PMID: 32851124; PMCID: PMC7423917. 4. Bridgeman VL, Wan E, Foo S, Nathan MR, Welti JC, Frentzas S, Vermeulen PB, Preece N, Springer CJ, Powles T, Nathan PD, Larkin J, Gore M, Vasudev NS, Reynolds AR. Preclinical Evidence That Trametinib Enhances the Response to Antiangiogenic Tyrosine Kinase Inhibitors in Renal Cell Carcinoma. Mol Cancer Ther. 2016 Jan;15(1):172-83. doi: 10.1158/1535-7163.MCT-15-0170. Epub 2015 Oct 20. PMID: 26487278.
In vitro protocol: 1. Itamura H, Shindo T, Tawara I, Kubota Y, Kariya R, Okada S, Komanduri KV, Kimura S. The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effects. JCI Insight. 2016 Jul 7;1(10):e86331. doi: 10.1172/jci.insight.86331. PMID: 27699218; PMCID: PMC5033881. 2. Bridgeman VL, Wan E, Foo S, Nathan MR, Welti JC, Frentzas S, Vermeulen PB, Preece N, Springer CJ, Powles T, Nathan PD, Larkin J, Gore M, Vasudev NS, Reynolds AR. Preclinical Evidence That Trametinib Enhances the Response to Antiangiogenic Tyrosine Kinase Inhibitors in Renal Cell Carcinoma. Mol Cancer Ther. 2016 Jan;15(1):172-83. doi: 10.1158/1535-7163.MCT-15-0170. Epub 2015 Oct 20. PMID: 26487278.
In vivo protocol: 1. Tada S, Anazawa T, Shindo T, Yamane K, Inoguchi K, Fujimoto N, Nagai K, Masui T, Okajima H, Takaori K, Sumi S, Uemoto S. The MEK Inhibitor Trametinib Suppresses Major Histocompatibility Antigen-mismatched Rejection Following Pancreatic Islet Transplantation. Transplant Direct. 2020 Aug 12;6(9):e591. doi: 10.1097/TXD.0000000000001045. PMID: 32851124; PMCID: PMC7423917. 2. Bridgeman VL, Wan E, Foo S, Nathan MR, Welti JC, Frentzas S, Vermeulen PB, Preece N, Springer CJ, Powles T, Nathan PD, Larkin J, Gore M, Vasudev NS, Reynolds AR. Preclinical Evidence That Trametinib Enhances the Response to Antiangiogenic Tyrosine Kinase Inhibitors in Renal Cell Carcinoma. Mol Cancer Ther. 2016 Jan;15(1):172-83. doi: 10.1158/1535-7163.MCT-15-0170. Epub 2015 Oct 20. PMID: 26487278.

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1. Vangala D, Ladigan S, Liffers ST, Noseir S, Maghnouj A, Götze TM, Verdoodt B, Klein-Scory S, Godfrey L, Zowada MK, Huerta M, Edelstein DL, de Villarreal JM, Marqués M, Kumbrink J, Jung A, Schiergens T, Werner J, Heinemann V, Stintzing S, Lindoerfer D, Mansmann U, Pohl M, Teschendorf C, Bernhardt C, Wolters H, Stern J, Usta S, Viebahn R, Admard J, Casadei N, Fröhling S, Ball CR, Siveke JT, Glimm H, Tannapfel A, Schmiegel W, Hahn SA. Secondary resistance to anti-EGFR therapy by transcriptional reprogramming in patient-derived colorectal cancer models. Genome Med. 2021 Jul 16;13(1):116. doi: 10.1186/s13073-021-00926-7. PMID: 34271981. 2.

1: Kasuga A, Nakagawa K, Nagashima F, Shimizu T, Naruge D, Nishina S, Kitamura H, Kurata T, Takasu A, Fujisaka Y, Okamoto W, Nishimura Y, Mukaiyama A, Matsushita H, Furuse J. A phase I/Ib study of trametinib (GSK1120212) alone and in combination with gemcitabine in Japanese patients with advanced solid tumors. Invest New Drugs. 2015 Aug 12. [Epub ahead of print] PubMed PMID: 26259955.

2: Giurcaneanu C, Nitipir C, Popa LG, Forsea AM, Popescu I, Bumbacea RS. Evolution of Melanocytic Nevi under Vemurafenib, Followed by Combination Therapy with Dabrafenib and Trametinib for Metastatic Melanoma. Acta Dermatovenerol Croat. 2015 Jul;23(2):87-95. Review. PubMed PMID: 26228819.

3: Modak S, Asante-Korang A, Steinherz LJ, Grana N. Trametinib-induced Left Ventricular Dysfunction in a Child With Relapsed Neuroblastoma. J Pediatr Hematol Oncol. 2015 Aug;37(6):e381-3. doi: 10.1097/MPH.0000000000000364. PubMed PMID: 26181424.

4: Schick U, Kyula J, Barker H, Patel R, Zaidi S, Gregory C, Hafsi H, Roulstone V, Deutsch E, McLaughlin M, Harrington K. Trametinib radiosensitises RAS- and BRAF-mutated melanoma by perturbing cell cycle and inducing senescence. Radiother Oncol. 2015 Jul 8. pii: S0167-8140(15)00323-0. doi: 10.1016/j.radonc.2015.06.026. [Epub ahead of print] PubMed PMID: 26163092.

5: Chopra N, Nathan PD. Trametinib in metastatic melanoma. Expert Rev Anticancer Ther. 2015;15(7):749-60. doi: 10.1586/14737140.2015.1060127. PubMed PMID: 26107021.

6: Melanoma: Dabrafenib and trametinib improve overall survival. Nat Rev Clin Oncol. 2015 Sep;12(9):502. doi: 10.1038/nrclinonc.2015.114. Epub 2015 Jun 23. PubMed PMID: 26099986.

7: Draganova D, Kerger J, Caspers L, Willermain F. Severe bilateral panuveitis during melanoma treatment by Dabrafenib and Trametinib. J Ophthalmic Inflamm Infect. 2015 Jun 9;5:17. doi: 10.1186/s12348-015-0049-9. eCollection 2015. PubMed PMID: 26078801; PubMed Central PMCID: PMC4460117.

8: Menzies AM, Yeh I, Botton T, Bastian BC, Scolyer RA, Long GV. Clinical activity of the MEK inhibitor trametinib in metastatic melanoma containing BRAF kinase fusion. Pigment Cell Melanoma Res. 2015 Sep;28(5):607-10. doi: 10.1111/pcmr.12388. Epub 2015 Jul 3. PubMed PMID: 26072686; PubMed Central PMCID: PMC4539279.

9: Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, Chiarion-Sileni V, Lebbe C, Mandalà M, Millward M, Arance A, Bondarenko I, Haanen JB, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, DeMarini DJ, Irani JG, Swann S, Legos JJ, Jin F, Mookerjee B, Flaherty K. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015 Aug 1;386(9992):444-51. doi: 10.1016/S0140-6736(15)60898-4. Epub 2015 May 31. PubMed PMID: 26037941.

10: Minor DR, Puzanov I, Callahan MK, Hug BA, Hoos A. Severe gastrointestinal toxicity with administration of trametinib in combination with dabrafenib and ipilimumab. Pigment Cell Melanoma Res. 2015 Sep;28(5):611-2. doi: 10.1111/pcmr.12383. Epub 2015 Jun 23. PubMed PMID: 25996827.

11: Escandell I, Cabezas M, Martín JM, Terradez L, Pinazo MI. Effective treatment with Dabrafenib and Trametinib for a BRAF-mutated metastatic dedifferentiated malignant spindle cell neoplasm. J Eur Acad Dermatol Venereol. 2015 Apr 27. doi: 10.1111/jdv.13155. [Epub ahead of print] PubMed PMID: 25917403.

12: Qiu JG, Zhang YJ, Li Y, Zhao JM, Zhang WJ, Jiang QW, Mei XL, Xue YQ, Qin WM, Yang Y, Zheng DW, Chen Y, Wei MN, Shi Z. Trametinib modulates cancer multidrug resistance by targeting ABCB1 transporter. Oncotarget. 2015 Jun 20;6(17):15494-509. PubMed PMID: 25915534.

13: Fujishita T, Kajino-Sakamoto R, Kojima Y, Taketo MM, Aoki M. Antitumor activity of the MEK inhibitor trametinib on intestinal polyp formation in Apc(Δ716) mice involves stromal COX-2. Cancer Sci. 2015 Jun;106(6):692-9. doi: 10.1111/cas.12670. Epub 2015 May 1. PubMed PMID: 25855137.

14: Rissmann R, Hessel MH, Cohen AF. Vemurafenib/dabrafenib and trametinib. Br J Clin Pharmacol. 2015 Apr 6. doi: 10.1111/bcp.12651. [Epub ahead of print] PubMed PMID: 25847075.

15: Thota R, Johnson DB, Sosman JA. Trametinib in the treatment of melanoma. Expert Opin Biol Ther. 2015 May;15(5):735-47. doi: 10.1517/14712598.2015.1026323. Epub 2015 Mar 26. PubMed PMID: 25812921.

16: Schadendorf D, Amonkar MM, Stroyakovskiy D, Levchenko E, Gogas H, de Braud F, Grob JJ, Bondarenko I, Garbe C, Lebbe C, Larkin J, Chiarion-Sileni V, Millward M, Arance A, Mandalà M, Flaherty KT, Nathan P, Ribas A, Robert C, Casey M, DeMarini DJ, Irani JG, Aktan G, Long GV. Health-related quality of life impact in a randomised phase III study of the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma. Eur J Cancer. 2015 May;51(7):833-40. doi: 10.1016/j.ejca.2015.03.004. Epub 2015 Mar 17. PubMed PMID: 25794603.

17: Blumenschein GR Jr, Smit EF, Planchard D, Kim DW, Cadranel J, De Pas T, Dunphy F, Udud K, Ahn MJ, Hanna NH, Kim JH, Mazieres J, Kim SW, Baas P, Rappold E, Redhu S, Puski A, Wu FS, Jänne PA. A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC)†. Ann Oncol. 2015 May;26(5):894-901. doi: 10.1093/annonc/mdv072. Epub 2015 Feb 26. PubMed PMID: 25722381.

18: Joshi M, Rice SJ, Liu X, Miller B, Belani CP. Trametinib with or without vemurafenib in BRAF mutated non-small cell lung cancer. PLoS One. 2015 Feb 23;10(2):e0118210. doi: 10.1371/journal.pone.0118210. eCollection 2015. PubMed PMID: 25706985; PubMed Central PMCID: PMC4338247.

19: Du SL, Yuan X, Zhan S, Tang LJ, Tong CY. Trametinib, a novel MEK kinase inhibitor, suppresses lipopolysaccharide-induced tumor necrosis factor (TNF)-α production and endotoxin shock. Biochem Biophys Res Commun. 2015 Mar 13;458(3):667-73. doi: 10.1016/j.bbrc.2015.01.160. Epub 2015 Feb 13. PubMed PMID: 25684183.

20: Mas C, Boda B, CaulFuty M, Huang S, Wiszniewski L, Constant S. Antitumour efficacy of the selumetinib and trametinib MEK inhibitors in a combined human airway-tumour-stroma lung cancer model. J Biotechnol. 2015 Jul 10;205:111-9. doi: 10.1016/j.jbiotec.2015.01.012. Epub 2015 Jan 20. PubMed PMID: 25615947.

(Last Updated: 4/21/2016)

Trametinib

200.0mg / USD 150.0


Additional Information

Antitumor activities: . Trametinib (JTP-74057) strongly inhibited MEK1/2 kinase activities, but did not inhibit another 98 kinase activities. Treatment by JTP-74057 resulted in growth inhibition accompanied with upregulation of p15INK4b and/or p27KIP1 in most of the colorectal cancer cell lines tested. Daily oral administration of JTP-74057 for 14 days suppressed tumor growth of HT-29 and COLO205 xenografts in nude mice. Notably, tumor regression was observed only in COLO205 xenografts, and COLO205 was much more sensitive to JTP-74057-induced apoptosis than HT-29 in vitro. Treatment with an Akt inhibitor enhanced the JTP-74057-induced apoptosis in HT-29 cells. Finally, JTP-74057 exhibited an additive or a synergistic effect in combination with the standard-of-care agents, 5-fluorouracil, oxaliplatin or SN-38. JTP-74057, a highly specific and potent MEK1/2 inhibitor, exerts favorable antitumor activities in vitro and in vivo. Sensitivity to JTP-74057-induced apoptosis may be an important factor for the estimation of in vivo efficacy, and sensitivity was enhanced by an Akt inhibitor. These results suggest the usefulness of JTP-74057 in therapeutic applications for colorectal cancer patients. (source: Int J Oncol. 2011 Jul;39(1):23-31).