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Purity: ≥98%
ETC-206 is a novel, potent and selective MNK1/2 inhibitor with IC50 of 64 nM for MNK1 and IC50 of 84 nM for MNK2. ETC-206 prevents BC-CML LSC self-renewal in vitro and boosts dasatinib antitumor activity in vivo when used in combination with the drug.
| Targets |
MNK1 (IC50 = 64 nM); MNK2 (IC50 = 86 nM)
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|---|---|
| ln Vitro |
In the HeLa cell line, tinodasertib (ETC-206) inhibits eIF4E phosphorylation with an IC50 of 321 nM. The CellTiter-Glo viability assay was used in vitro to assess the anti-stress effects of ETC-206 against 25 blood cell lines, including the K562 cell line that overexpresses cardiovascular eIF4E (K562 o/ e eIF4E). for Ramos.2G6.4C10, AHH-1, MC 116, P3HR-1, DOHH2, MPC-11, SU-DHL-6, GK-5, and K562 o/e eIF4E cells [1].
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| ln Vivo |
Next, using the K562 e/o eIF4E mouse xenograft model, the antitumor effects of ETC-206 were assessed. The drug was administered lateralized at 25, 50, or 100 mg/kg either by itself or in combination with a fixed dose of dasatinib at 2.5 mg/kg for the duration of the study. following the union. A dose of 2.5 mg/kg of dasatinib resulted in 88% tumor growth inhibition (TGI). Conversely, at the highest dose of 100 mg/kg, ETC-206 produced only 23 % of the maximum TGI, which was comparable to untreated animals and did not inhibit tumor growth. More significantly, 2, 5 of the 8 animals at 25, 50, and 100 mg/kg and 8 were tumor-free when ETC-206 and dasatinib at 2.5 mg/kg were combined. This increased tumor growth inhibition in a dose-dependent manner. kilograms, in that order. At all tested doses, the combination of dasatinib and ETC-206 inhibited tumor growth; no weight loss was observed. In syngeneic mouse xenograft models, the combination of dasatinib and ETC-206, as well as dual MNK1/2 and BCR-ABL1, inhibited tumor growth. The terminal elimination half-life of ETC-206 is regulated and is 1.77 hours for mice given 5 mg/kg po and t1/2=1.7 hours for mice given 1 mg/kg iv[1].
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| Cell Assay |
ETC-206's ability to inhibit cell proliferation in 25 hematological cancer cell lines, including the K562 cell line that overexpresses eIF4E (K562 o/e eIF4E), is tested in vitro using the CellTiter-Glo viability assay. Generally speaking, the IC50 values fall into the micromolar range[1].
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| Animal Protocol |
Mice: CD-1 female mice (6-8 weeks old) are weighed, and those selected for dosing are 24±2 g. Each group of three mice is chosen at random. ETC-206 is given to mice as a single injection into a tail vein at a dose of 1 mg/kg or as a single oral gavage at a dose of 5 mg/kg. 4 mL/kg and 8 mL/kg, respectively, are the injection volumes for intravenous (i.v.) and oral (p.o.) administration[1].
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| References | |
| Additional Infomation |
Tinodasertib is a selective mitogen-activated protein kinase (MAPK)-interacting protein kinase (MNK) types 1/2 inhibitor with potential antineoplastic activity. Upon administration, tinodasertib may inhibit MNK1/2-dependent phosphorylation of eukaryotic initiation factor 4E (eIF4E) and interfere with its role in mRNA translation. eIF4E is an oncoprotein that must be phosphorylated before it can promote the proliferation and progression of tumor cells. MNKs are a family of serine/threonine kinases that have been implicated in oncogenic transformation and tumor progression.
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| Molecular Formula |
C25H20N4O2
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|---|---|
| Molecular Weight |
408.45
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| Exact Mass |
408.16
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| Elemental Analysis |
C, 73.51; H, 4.94; N, 13.72; O, 7.83
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| CAS # |
1464151-33-4
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| Related CAS # |
1464151-33-4
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| PubChem CID |
71766360
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
3.9
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
31
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| Complexity |
668
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
FWRFPHJSGLYXTD-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H20N4O2/c26-15-18-1-3-20(4-2-18)23-16-27-24-10-9-22(17-29(23)24)19-5-7-21(8-6-19)25(30)28-11-13-31-14-12-28/h1-10,16-17H,11-14H2
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| Chemical Name |
4-[6-[4-(morpholine-4-carbonyl)phenyl]imidazo[1,2-a]pyridin-3-yl]benzonitrile
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| Synonyms |
Tinodasertib; ETC-206; ETC 206; ETC206
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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: ~82 mg/mL (~200.8 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5 mg/mL (12.24 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 50.0 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: ≥ 5 mg/mL (12.24 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 50.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 5 mg/mL (12.24 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4483 mL | 12.2414 mL | 24.4828 mL | |
| 5 mM | 0.4897 mL | 2.4483 mL | 4.8966 mL | |
| 10 mM | 0.2448 mL | 1.2241 mL | 2.4483 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03414450 | Withdrawn | Drug: ETC-1907206 Drug: dasatinib |
Ph+ Acute Lymphoblastic Leukemia (Ph+ALL) Ph- Acute Lymphoblastic Leukemia (Ph-ALL) |
EDDC (Experimental Drug Development Centre), A*STAR Research Entities |
April 25, 2018 | Phase 1 |
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