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Ensartinib (formerly known as X-396) is a novel, highly potent, selective, and orally available small molecule inhibitor of ALK (anaplastic lymphoma kinase) with an IC50 less than 4 nM in Ambit assays. It is an additional activity MET, ABL, Axl, EPHA2, LTK, ROS1, and SLK tyrosine kinase inhibitor (TKI). Although higher concentrations are needed to prevent autophosphorylation of the wild-type fusion, ensartinib significantly reduces ALK autophosphorylation. When ALK-expressing tumor cells are inhibited, ALK-mediated signaling is disrupted, which ultimately stops tumor cell growth. Consequently, ensartinib may have anticancer effects.
| ln Vitro |
Ensartinib (X-396) dihydrochloride has dual ALK/MET inhibitory activity and a potent IC50 of less than 0.4 nM and 0.74 nM, respectively. In H3122 lung cancer cells expressing EML4-ALK E13;A20, ensetinib dihydrochloride exhibits potency (IC50: 15 nM). In H2228 lung cancer cells expressing EML4-ALK E6a/b; A20, esartinib dihydrochloride is likewise effective (IC50: 45 nM). Moreover, X-376 has a high potency (IC50: 9 nM) in SUDHL-1 lymphoma cells that harbor NPM-ALK.
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| ln Vivo |
Ensartinib exhibits significant bioavailability and moderate half-lives in vivo, according to a pharmacokinetic analysis. Examined are Ensartinib (X-396)'sinvivo effects on H3122 xenografts. Ensartinib, 25 mg/kg bid, is administered to nude mice containing H3122 xenografts. When compared to the vehicle alone, ensartinib considerably slows the growth of tumors. Ensartinib appears to be well-tolerated in vivo in the xenograft experiments. Treatment with ensartinib has no effect on mouse weight. Mice given drugs seem healthy and do not show any symptoms of toxicity from the compounds. Additional systemic toxicity and toxico-kinetic studies are carried out in Sprague Dawley (SD) rats to further evaluate potential side effects of ensartinib. After ten days of repeated oral administration of Ensartinib at doses of 20, 40, and 80 mg/kg in SD rats, every animal survives to the end of the study. Ensartinib has been found to have a no significant toxicity (NST) level of 80 mg/kg. Ensartinib has an AUC of 66 μMΗhr and a Cmax of 7.19 μM at NST levels[1].
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| Cell Assay |
In 96-well plates, cells are seeded at 25%–33% confluency and exposed to medications for viability experiments. Ensartinib (10, 30, 100, 300, and 1000 nM) is used to treat the human lung adenocarcinoma cell lines H3122 and H2228. Ensartinib (5, 10, 30, 100, and 300 nM) is used to treat SUDHL-1 lymphoma cells. Ensartinib (30, 100, 300, and 1000 nM) is used to treat SY5Y neuroblastoma cells. After adding Ensartinib for 72 hours, Cell Titer Blue Reagent is added, and the Spectramax spectrophotometer is used to measure the fluorescence. Every experimental point is set up in duplicate three times, and it is run at least twice independently. GraphPad Prism version 5 for Windows is used to calculate IC50s. With a log (inhibitor) vs. response formula, a nonlinear regression model is used to fit the curves[1].
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| Animal Protocol |
Mice: H3122 cells are injected into naked mice (nu/nu). Following the tumors' average volume of 450 mm3, 27 athymic mice with H3122 tumors are randomly assigned to receive either the control vehicle or 25 mg/kg of ensartinib orally via gavage. Mice are killed two, five, and fifteen hours after the single treatment (3 tumors/timepoint/group), and serum is taken for an LC-MS based bioanalytical method to determine the drug concentration[1].
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| References |
| Molecular Formula |
C26H29CL4FN6O3
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|---|---|
| Molecular Weight |
634.357265233994
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| Exact Mass |
634.1
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| Elemental Analysis |
C, 49.23; H, 4.61; Cl, 22.35; F, 2.99; N, 13.25; O, 7.57
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| CAS # |
2137030-98-7
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| Related CAS # |
Ensartinib;1370651-20-9
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| PubChem CID |
138320013
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| Appearance |
White to light yellow solid powder
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
40
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| Complexity |
812
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| Defined Atom Stereocenter Count |
3
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| SMILES |
C[C@@H]1CN(C[C@@H](N1)C)C(=O)C2=CC=C(C=C2)NC(=O)C3=NN=C(C(=C3)O[C@H](C)C4=C(C=CC(=C4Cl)F)Cl)N.Cl.Cl
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| InChi Key |
IERUINQRGJAECT-ISUJJMBGSA-N
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| InChi Code |
InChI=1S/C26H27Cl2FN6O3.2ClH/c1-13-11-35(12-14(2)31-13)26(37)16-4-6-17(7-5-16)32-25(36)20-10-21(24(30)34-33-20)38-15(3)22-18(27)8-9-19(29)23(22)28;;/h4-10,13-15,31H,11-12H2,1-3H3,(H2,30,34)(H,32,36);2*1H/t13-,14+,15-;;/m1../s1
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| Chemical Name |
6-amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-N-[4-[(3R,5S)-3,5-dimethylpiperazine-1-carbonyl]phenyl]pyridazine-3-carboxamide;dihydrochloride
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| Synonyms |
X-396 hydrochloride; X396 hydrochloride; X 396 hydrochloride; Ensartinib dihydrochloride; Ensartinib HCl; Ensartinib hydrochloride
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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 : ~35.71 mg/mL (~56.29 mM)
H2O : ~33.33 mg/mL (~52.54 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.28 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 20.8 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: ≥ 2.08 mg/mL (3.28 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 20.8 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: ≥ 2.08 mg/mL (3.28 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 14.29 mg/mL (22.53 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5764 mL | 7.8820 mL | 15.7639 mL | |
| 5 mM | 0.3153 mL | 1.5764 mL | 3.1528 mL | |
| 10 mM | 0.1576 mL | 0.7882 mL | 1.5764 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 |
| NCT05665283 | Not yet recruiting | Drug: Ensartinib Hydrochloride | Non Small Cell Lung Cancer | Xcovery Holding Company, LLC | January 1, 2023 | Phase 1 |
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