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Purity: ≥98%
Trametinib (GSK1120212; JTP74057; Trade name: Mekinist), an FDA-approved anti-melanoma medication, is a novel, highly specific, and orally bioactive MEK1/2 inhibitor with potential antineoplastic activity. In cell-free assays, it inhibits MEK1/2 with IC50 values of 0.92 nM/1.8 nM and exhibits little to no inhibition of other kinases like c-Raf, B-Raf, and ERK1/2. Trametinib was initially thought to be a p15 inductive substance, but it was later discovered to be an allosteric inhibitor of MEK kinase. When used against MEK1 and MEK2 kinase, trametinib exhibits ATP non-competitive inhibition. Trametinib binds to and specifically inhibits MEK 1 and 2, which prevents growth factor-mediated cell signaling and cellular proliferation in a variety of cancers. The RAS/RAF/MEK/ERK signaling pathway, which controls cell growth, is activated by the dual specificity threonine/tyrosine kinases MEK 1 and 2. These kinases are frequently upregulated in different cancer cell types. On May 29, 2013, the FDA granted Trametinib approval to treat melanoma.
| Targets |
MEK1 (IC50 = 0.92 nM); MEK2 (IC50 = 1.8 nM)
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| ln Vitro |
GSK1120212 has an IC50 range of 0.92 nM to 3.4 nM and inhibits the phosphorylation of MBP regardless of the isotypes of Raf and MEK. c-Raf, B-Raf, ERK1 and ERK2 are not inhibited by GSK1120212's kinase activity. Furthermore, the other 98 kinases are not significantly inhibited by GSK1120212 in a significant way. The human colorectal cancer cell lines are effectively inhibited by GSK1120212. The cells with the highest sensitivity to GSK1120212 have IC50 values of 0.48 nM and 0.52 nM, respectively, and are known to have a constitutively active B-Raf mutant in HT-29 and COLO205. With an IC50 range of 2.2–174 nM, the cell lines with the K-Ras mutation exhibit a wide range of sensitivity to GSK1120212. The wild-type gene in both B-Raf and K-Ras is present in COLO320 DM cells, which are resistant to GSK1120212 even at 10 μM. All sensitive cell lines experience cell-cycle arrest at the G1 phase after a 24-hour treatment with GSK1120212. p15INK4b and/or p27KIP1 are consistently upregulated by GSK1120212 treatment in the majority of colorectal cancer cell lines. ERK phosphorylation by GSK1120212 is inhibited in all susceptible cell lines. Both HT-29 and COLO205 cells experience apoptosis induction from GSK1120212; however, COLO205 cells are more vulnerable to this induction than HT-29 cells are. [1] Peripheral blood mononuclear cells (PBMCs) cannot produce tumor necrosis factor or interleukin-6 because GSK1120212 inhibits this process. [2]
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| ln Vivo |
GSK1120212 can effectively stop the growth of the HT-29 xenograft when given orally at doses of 0.3 mg/kg or 1 mg/kg once daily for 14 days. At doses of 1 mg/kg, the tumor growth is almost entirely stopped. A single oral dose of 1 mg/kg GSK1120212 completely inhibits the phosphorylation of ERK1/2 in the tissues of established tumors, and after 14 days of treatment, the levels of the proteins p15INK4b and p27KIP1 are both increased. Tumor regression is seen in the COLO205 xenograft model even at a dose of 0.3 mg/kg. Four out of six mice receiving a dose of 1 mg/kg experience a complete regression, in which the tumor has regressed to the point where its volume is no longer detectable. [1] Adjuvant-induced arthritis (AIA) and type II collagen-induced arthritis (CIA) in Lewis rats or DBA1/J mice, respectively, are almost completely suppressed after administration of GSK1120212 at 0.1 mg/kg. [2]
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| Enzyme Assay |
The active form of B-Raf/c-Raf, unphosphorylated MEK1/MEK2, and ERERK2, as well as non-phosphorylated myelin basic protein (MBP), are combined with MOPS buffer containing 12.5 mM MgCl2 and 10 μM ATP in the presence of varying concentrations of GSK1120212. The anti-phospho-MBP antibody can spot MBP that has been phosphorylated.
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| Cell Assay |
In 96-well tissue culture plates, exponentially growing cells are precultured for 24 hours before being exposed to GSK1120212. An in vitro toxicology assay kit based on sulforhodamine B measures cell growth. Both adherent and floating cells are collected for the apoptosis assay and fixed with 70% ethanol. The cells are then washed with PBS, suspended in 100 μg/mL RNase and 25 μg/mL propidium iodide (PI), and heated to 37 °C for 30 minutes while kept in the dark. The Cytomics FC500 or Guava EasyCyte plus flow cytometer is used to measure the DNA content of each individual cell.
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| Animal Protocol |
Mice: The mice used are BALB/c-nu/nu females. HT-29 cells or COLO205 cells suspended in ice-cold HBSS (-) are subcutaneously injected into the right flank of the mice on day 0 at a density of 5×106 cells/100 µL/site or 1×106 cells per 100 µL, respectively. When the mean tumor volume reaches 100 mm3, the acetic acid-solvated form of Trametinib (JTP-74057, 0.3 mg/kg, or 1 mg/kg) is dissolved in 10% Cremophor EL-10% PEG400 and given orally once daily for 14 days. Two weeks after the start of dosing, the tumor's length [L(mm)] and width [W(mm)] are measured using a microgauge, and the tumor's volume is calculated using the formula tumor volume (mm3)=L×W×W/2.
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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Following oral administration, trametinib is rapidly and readily absorbed. The absorption was examined in patients with solid tumours and BRAF V600 mutation-positive metastatic melanoma. Following the administration of trametinib tablets 0.125 mg (0.0625 times the approved recommended adult dosage) to 4 mg (2 times the approved recommended adult dosage) daily, both Cmax and AUC increased dose-proportionally. Intersubject variability in AUC and Cmax at steady state is 22% and 28%, respectively. Trametinib accumulates with daily repeat dosing with a mean accumulation ratio of 6.0 at 2 mg once daily dose. Steady-state was achieved by Day 15. The mean absolute bioavailability of trametinib is 72% for oral tablets and 81% for oral solution. The Tmax is 1.5 hours. A high-fat, high-calorie meal (approximately 1000 calories) decreased trametinib AUC by 24% and Cmax by 70%, and delayed Tmax by approximately four hours as compared with fasted conditions. Following oral administration of [14C]-trametinib, greater than 80% of excreted radioactivity was recovered in the feces while less than 20% of excreted radioactivity was recovered in the urine with less than 0.1% of the excreted dose as the parent molecule. The apparent volume of distribution (Vc/F) is 214 L. The apparent clearance is 4.9 L/h. Metabolism / Metabolites Trametinib predominantly undergoes deacetylation mediated by carboxylesterases (i.e., carboxylesterase 1b/c and 2) and other hydrolytic enzymes. The deacetylated metabolite may further be glucuronidated. _In vitro_ findings suggest that deacetylation may also be accompanied by mono-oxygenation, hydroxylation, and glucuronidation. CYP3A4-mediated oxidation is a minor pathway. Four metabolites (M1/2/3/4) have been characterized in patients with advanced cancers. _In vitro_, the M1 and M3 metabolites demonstrated approximately equal or 10-fold less potent phospho-MEK1-inhibiting activity than the parent compound. Following a single dose of [14C]-trametinib, approximately 50% of circulating radioactivity represented the parent compound. According to findings from metabolite profiling after repeat dosing of trametinib, unchanged parent drug accounted for greater than or equal to 75% of drug-related material in plasma. Biological Half-Life The estimated elimination half-life is 3.9 to 4.8 days. |
| Toxicity/Toxicokinetics |
Hepatotoxicity
In large clinical trials, abnormalities in routine liver tests were common with serum aminotransferase elevations occurring in 39% to 60% and alkaline phosphatase in 24% to 67% of patients treated with trametinib. However, elevations in ALT above 5 times the ULN were uncommon, occurring in 0% to 5% of patients and generally resolving rapidly with temporary discontinuation or dose adjustment. In the prelicensure controlled trials of trametinib with or without dabrafenib, no cases of clinically apparent acute liver injury or hepatic failure were reported. There have yet to be published cases of clinically apparent hepatotoxicity attributed to trametinib. However, it has been used for a short time only. Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation No information is available on the clinical use of trametinib during breastfeeding. Because trametinib is 97% bound to plasma proteins, the amount in milk is likely to be low. However, its half-life is 3.9 to 4.8 days and it might accumulate in the infant. The manufacturer recommends that breastfeeding be discontinued during trametinib therapy and for 4 months after the last dose. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding Trametinib is 97.4% bound to human plasma proteins. |
| References | |
| Additional Infomation |
Pharmacodynamics
Trametinib inhibits cell growth of various BRAF V600 mutation-positive tumours _in vitro_ and _in vivo_. Trametinib is often used in combination with dabrafenib, a BRAF inhibitor. In BRAF-mutant colorectal cancer, induction of EGFR-mediated MAPK pathway re-activation has been identified as a mechanism of intrinsic resistance to BRAF inhibitors. The MAPK pathway is one of the most important pathways for novel anticancer drug development. We performed high-throughput screening for compounds that induce expression of p15INK4b, and identified JTP-74057 (GSK1120212), which is being evaluated in ongoing phase I, II and III clinical trials. We characterized its antitumor activities in vitro and in vivo. 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.[1] Objective and design: To examine the effects of a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2-inhibitor, JTP-74057, on inflammatory arthritis development, and compare its anti-arthritic effect with leflunomide. Materials: Human, mouse, and rat peripheral blood mononuclear cells (PBMCs) were used. Lewis rats and DBA/1J mice were used for animal models. Treatment: JTP-74057 was tested between 0.1-100 nM in in-vitro studies. JTP-74057 (0.01-0.3 mg/kg) and leflunomide (2-10 mg/kg) were administered orally in vivo. Methods: PBMCs were stimulated with lipopolysaccharide. Adjuvant-induced arthritis (AIA) and type II collagen-induced arthritis (CIA) was induced in Lewis rats or DBA1/J mice, respectively. Results: JTP-74057 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, JTP-74057, but not leflunomide, suppressed collagen-reactive T-cell proliferation ex vivo, whereas leflunomide, but not JTP-74057, suppressed anti-collagen antibody production. Conclusions: JTP-74057 exerts potent anti-arthritic effects with a different profile from leflunomide, suggesting that JTP-74057 may be useful as a new therapeutic reagent in the treatment of rheumatoid arthritis.[2] Recent results from clinical trials with the BRAF inhibitors GSK2118436 (dabrafenib) and PLX4032 (vemurafenib) have shown encouraging response rates; however, the duration of response has been limited. To identify determinants of acquired resistance to GSK2118436 and strategies to overcome the resistance, we isolated GSK2118436 drug-resistant clones from the A375 BRAF(V600E) and the YUSIT1 BRAF(V600K) melanoma cell lines. These clones also showed reduced sensitivity to the allosteric mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor GSK1120212 (trametinib). Genetic characterization of these clones identified an in-frame deletion in MEK1 (MEK1(K59del)) or NRAS mutation (NRAS(Q61K) and/or NRAS(A146T)) with and without MEK1(P387S) in the BRAF(V600E) background and NRAS(Q61K) in the BRAF(V600K) background. Stable knockdown of NRAS with short hairpin RNA partially restored GSK2118436 sensitivity in mutant NRAS clones, whereas expression of NRAS(Q61K) or NRAS(A146T) in the A375 parental cells decreased sensitivity to GSK2118436. Similarly, expression of MEK1(K59del), but not MEK1(P387S), decreased sensitivity of A375 cells to GSK2118436. The combination of GSK2118436 and GSK1120212 effectively inhibited cell growth, decreased ERK phosphorylation, decreased cyclin D1 protein, and increased p27(kip1) protein in the resistant clones. Moreover, the combination of GSK2118436 or GSK1120212 with the phosphoinositide 3-kinase/mTOR inhibitor GSK2126458 enhanced cell growth inhibition and decreased S6 ribosomal protein phosphorylation in these clones. Our results show that NRAS and/or MEK mutations contribute to BRAF inhibitor resistance in vitro, and the combination of GSK2118436 and GSK1120212 overcomes this resistance. In addition, these resistant clones respond to the combination of GSK2126458 with GSK2118436 or GSK1120212. Clinical trials are ongoing or planned to test these combinations.[3] |
| Molecular Formula |
C26H23FIN5O4
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|---|---|
| Molecular Weight |
615.39
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| Exact Mass |
615.077
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| Elemental Analysis |
C, 50.74; H, 3.77; F, 3.09; I, 20.62; N, 11.38; O, 10.40
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| CAS # |
871700-17-3
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| Related CAS # |
Trametinib (DMSO solvate);1187431-43-1;Trametinib-d4;Trametinib-13C6;Trametinib-13C,d3;2712126-59-3
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| PubChem CID |
11707110
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| Appearance |
white solid powder
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| Density |
1.7±0.1 g/cm3
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| Index of Refraction |
1.734
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| LogP |
2.68
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
37
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| Complexity |
1090
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C)NC1C=C(N2C3C(=C(N(C)C(C=3C)=O)NC3C(F)=CC(I)=CC=3)C(=O)N(C3CC3)C2=O)C=CC=1
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| InChi Key |
LIRYPHYGHXZJBZ-UHFFFAOYSA-N
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| 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)
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| 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
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| Synonyms |
JTP-74057; GSK 1120212; GSK1120212; GSK-1120212; JTP74057; Trametinib. Trade name: Mekinist
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.06 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.06 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: 4% DMSO+corn oil: 3mg/mL Solubility in Formulation 4: 6.67 mg/mL (10.84 mM) in 0.5%HPMC 1%Tween80 (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6250 mL | 8.1249 mL | 16.2499 mL | |
| 5 mM | 0.3250 mL | 1.6250 mL | 3.2500 mL | |
| 10 mM | 0.1625 mL | 0.8125 mL | 1.6250 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Platform Study of JDQ443 in Combinations in Patients With Advanced Solid Tumors Harboring the KRAS G12C Mutation
CTID: NCT05358249
Phase: Phase 1/Phase 2 Status: Active, not recruiting
Date: 2024-11-15
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Products are for research use only; We do not sell to patients
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