| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| 5mg |
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| 10mg |
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| Other Sizes |
| Targets |
MEK1 MEK2
MEK (both KSR-bound and RAF-bound forms) |
|---|---|
| ln Vitro |
On KSR-bound MEK, trametiglue preserves trametinib's potent binding ability and residence duration [1]. In contrast to trametinib, but akin to avitometinib, trametiglue improves the relationship between endogenous BRAF and MEK1 [1]. Direct binding tests show that metetipleniglue (1 μM) is very selective for MEK1 and MEK2. Trametiglue exhibits a high degree of selectivity when it comes to a class of active kinases that either directly phosphorylate MEK1 or MEK2 substrates or prevent upstream kinases from doing so [1]. HCT116, A375, A549, and SK-MEL-239 cells' viability is inhibited by metamiglue (5 days) with IC50 values of 0.07, 0.07, 0.12, and 0.47 nM, respectively[1]. More potently than trametinib, trametiglue (10 nM; 10 days) suppresses the development of colonies in cancer cells with mutant BRAF and KRAS [1].
Trametiglue exhibits exceptional potency and selectivity in targeting KSR‑MEK and RAF‑MEK through unique interfacial binding interactions. It demonstrates significantly enhanced inhibition of RAS/ERK signaling versus trametinib in various cell lines with mutant KRAS and BRAF. Trametiglue displays no direct interaction with BRAF or CRAF, confirming its strong selectivity towards MEK. |
| ln Vivo |
Trametiglue provides durable inhibition of RAS/ERK signaling in models of mutant KRAS and BRAF. It limits adaptive resistance seen with trametinib via enhanced interfacial binding, acting as a molecular glue that traps inactive states of RAF-bound MEK. This mechanism overcomes KSR-mediated adaptive resistance, leading to sustained pathway suppression.
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| Enzyme Assay |
Trametiglue is a derivative of trametinib modified to enhance interfacial binding. For non‑cellular assays, recombinant MEK1/2 proteins are incubated with trametiglue (0.1‑1000 nM) in the presence of ATP, and kinase activity is measured using a coupled enzymatic assay or by quantifying phosphorylated ERK substrate via fluorescence or luminescence detection.
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| Cell Assay |
Cell Viability Assay[1]
Cell Types: SK-MEL-239, HCT116, A549 and A375 Tested Concentrations: Incubation Duration: 5 days Experimental Results: demonstrated IC50s of 0.47, 0.07, 0.12 and 0.07 nM against SK-MEL-239, HCT116, A549 and A375 cells, respectively. Western Blot Analysis[1] Cell Types: A549, HCT-116, A375 and SK-MEL-239 Tested Concentrations: 0.4, 0.8, 1.6, 3.1, 6.25, 12.5, 25 and 50 nM Incubation Duration: 1 h Experimental Results: Inhibited the expression of pERK. And the effect was better than Trametinib. Trametiglue is dissolved in DMSO and diluted to desired concentrations. Cells harboring KRAS or BRAF mutations (e.g., HCT116, A549) are treated with trametiglue (1 nM - 10 uM) for 2‑24 h. ERK phosphorylation is measured by Western blotting or phospho‑ERK ELISA. Cell proliferation is assessed by MTT or colony formation assays after 72 h. |
| Animal Protocol |
Trametiglue is formulated in a suitable vehicle (e.g., 10% DMSO, 40% PEG400, 5% Tween 80) and administered orally or intraperitoneally to mice bearing KRAS- or BRAF-mutant tumor xenografts (e.g., HCT116). Tumors and plasma are collected at multiple time points for PK/PD analysis, including measurement of phospho‑ERK levels and MEK target engagement.
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| ADME/Pharmacokinetics |
No detailed PK data for trametiglue has been reported. However, as a trametinib analog with enhanced interfacial binding, it is expected to maintain favorable oral bioavailability and metabolic stability. Detailed parameters such as half‑life, Cmax, and tissue distribution are not publicly available.
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| Toxicity/Toxicokinetics |
No detailed toxicity data for trametiglue has been reported. As a MEK inhibitor acting via a molecular glue mechanism, it may share class‑related adverse effects observed with other MEK inhibitors (e.g., rash, diarrhea, fatigue) when used systemically. No toxicology studies have been published to date.
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| References | |
| Additional Infomation |
Trametiglue was developed based on structural insights into trametinib's binding to KSR-bound MEK. It acts as a molecular glue that traps inactive states of RAF-bound MEK, limiting adaptive resistance commonly observed with trametinib monotherapy. This mechanism has implications for designing next‑generation drugs targeting the RAS pathway. No clinical trials or regulatory approvals have been reported.
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| Molecular Formula |
C25H24FIN6O5S
|
|---|---|
| Molecular Weight |
666.463139533997
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| Exact Mass |
666.055
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| CAS # |
2666940-97-0
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| PubChem CID |
154700547
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| Appearance |
White to light yellow solid powder
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| LogP |
2.9
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
39
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| Complexity |
1230
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S(NC1=CC=CC(N2C3=C(C)C(=O)N(C)C(NC4=CC=C(I)C=C4F)=C3C(=O)N(C3CC3)C2=O)=C1)(NC)(=O)=O
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| InChi Key |
DNNMBAWCLGMMRJ-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C25H24FIN6O5S/c1-13-21-20(22(31(3)23(13)34)29-19-10-7-14(27)11-18(19)26)24(35)33(16-8-9-16)25(36)32(21)17-6-4-5-15(12-17)30-39(37,38)28-2/h4-7,10-12,16,28-30H,8-9H2,1-3H3
|
| Chemical Name |
3-cyclopropyl-5-(2-fluoro-4-iodoanilino)-6,8-dimethyl-1-[3-(methylsulfamoylamino)phenyl]pyrido[4,3-d]pyrimidine-2,4,7-trione
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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) |
DMSO: 100 mg/mL (150.05 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (3.75 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5005 mL | 7.5023 mL | 15.0047 mL | |
| 5 mM | 0.3001 mL | 1.5005 mL | 3.0009 mL | |
| 10 mM | 0.1500 mL | 0.7502 mL | 1.5005 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.
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