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| 10mg |
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| 25mg |
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Purity: ≥98%
Ensartinib (formerly known as X-396) is a novel, highly potent and selective, orally available small molecule inhibitor of ALK (anaplastic lymphoma kinase) with an IC50 less than 4 nM in Ambit assays. It is a tyrosine kinase inhibitor (TKI) that inhibits ALK, as well as MET, ABL, Axl, EPHA2, LTK, ROS1, and SLK. Ensartinib considerably reduces ALK autophosphorylation, though greater concentrations are needed to prevent autophosphorylation of the wild-type fusion. ALK-mediated signaling is disrupted when ALK is inhibited, which ultimately stops tumor cell growth in tumor cells that express ALK. Thus, ensartinib may possess anticancer properties.
| Targets |
ALK (IC50 <0.4 nM); MET (IC50 = 0.74 nM)
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| ln Vitro |
Ensartinib (X-396) is tested for its capacity to suppress the growth of various cancer cell lines that carry point mutations or ALK fusions. The H3122 lung cancer cells that harbor EML4-ALK E13;A20 are susceptible to the potency of entartinib (IC50: 15nM). When H2228 lung cancer cells expressing EML4-ALK E6a/b; A20 are exposed to entartinib, it is also effective (IC50: 45 nM). In SUDHL-1 lymphoma cells that harbor NPM-ALK, X-376 is also effective (IC50: 9 nM). In addition, X-376 inhibits the following cell lines: HepG2, PC-9 lung cancer, MKN-45 gastric carcinoma, SY5Y neuroblastoma cells harboring ALK F1174L, and 68 nM, 156 nM, 9.644 μM, and 2.989 μM, respectively.
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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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| Enzyme Assay |
Ensartinib (also known as X-396) is a novel, potent and specific ALK TKI with the IC50 less than 4 nM in Ambit assays.
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| Cell Assay |
The following cells types are treated with ALK TKIs or vehicle for 72 hours: SUDHL-1 lymphoma cells with NPM-ALK fusion, H2228 lung cancer cells harboring the EML4-ALK E6a/b;A20 fusion, H3122 lung cancer cells containing the EML4-ALK E13;A20 fusion, and SY5Y neuroblastoma cells with an activating mutation within the ALK kinase domain (ALK F1174L). Growth inhibition is measured using cell titer blue assays.
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| Animal Protocol |
Mice: H3122 cells are injected into nude mice (nu/nu). Two groups of 27 athymic mice with H3122 tumors are randomly assigned to receive either the control vehicle or 25 mg/kg of ensartinib (X-396) orally via gavage once the tumors have reached an average volume of 450 mm3. Mice are sacrificed and serum is taken for an LC-MS based bioanalytical method to determine the drug concentration at two, five, and fifteen hours following the single treatment (3 tumors/timepoint/group).
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| References | |
| Additional Infomation |
Ensartinib is under investigation in clinical trial NCT03420508 (Treating Patients With Melanoma and ALK Alterations With Ensartinib).
Ensartinib is an orally available small molecule inhibitor of the receptor tyrosine kinase anaplastic lymphoma kinase (ALK) with potential antineoplastic activity. Upon oral administration, ensartinib binds to and inhibits ALK kinase, ALK fusion proteins and ALK point mutation variants. Inhibition of ALK leads to the disruption of ALK-mediated signaling and eventually inhibits tumor cell growth in ALK-expressing tumor cells. ALK belongs to the insulin receptor superfamily and plays an important role in nervous system development. ALK is not expressed in healthy adult human tissue but ALK dysregulation and gene rearrangements are associated with a series of tumors; ALK mutations are associated with acquired resistance to small molecule tyrosine kinase inhibitors. Drug Indication Treatment of non-small cell lung cancer |
| Molecular Formula |
C26H27CL2FN6O3
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|---|---|---|
| Molecular Weight |
561.44
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| Exact Mass |
560.15
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| Elemental Analysis |
C, 55.62; H, 4.85; Cl, 12.63; F, 3.38; N, 14.97; O, 8.55
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| CAS # |
1370651-20-9
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| Related CAS # |
Ensartinib dihydrochloride;2137030-98-7
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| PubChem CID |
56960363
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
708.0±60.0 °C at 760 mmHg
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| Flash Point |
382.0±32.9 °C
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| Vapour Pressure |
0.0±2.3 mmHg at 25°C
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| Index of Refraction |
1.629
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| LogP |
4.7
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
38
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| Complexity |
812
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| Defined Atom Stereocenter Count |
3
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| SMILES |
C1(C(NC2=CC=C(C(N3C[C@H](C)N[C@H](C)C3)=O)C=C2)=O)=NN=C(N)C(O[C@@H](C2=C(Cl)C=CC(F)=C2Cl)C)=C1
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| InChi Key |
GLYMPHUVMRFTFV-QLFBSQMISA-N
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| InChi Code |
InChI=1S/C26H27Cl2FN6O3/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)/t13-,14+,15-/m1/s1
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| Chemical Name |
6-amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-N-[4-[(3S,5R)-3,5-dimethylpiperazine-1-carbonyl]phenyl]pyridazine-3-carboxamide
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| Synonyms |
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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 |
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| 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) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7811 mL | 8.9057 mL | 17.8113 mL | |
| 5 mM | 0.3562 mL | 1.7811 mL | 3.5623 mL | |
| 10 mM | 0.1781 mL | 0.8906 mL | 1.7811 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 |
| NCT04837716 | Active Recruiting |
Drug: Ensartinib Drug: Carboplatin |
Stage IIIC Lung Cancer AJCC v8 Stage IV Lung Cancer AJCC v8 |
M.D. Anderson Cancer Center | March 18, 2021 | Phase 1 |
| NCT02767804 | Active Recruiting |
Drug: X-396 (ensartinib) Drug: crizotinib |
Non-small Cell Lung Cancer | Xcovery Holding Company, LLC | June 2016 | Phase 3 |
| NCT05491811 | Not yet recruiting | Drug: Ensartinib Drug: Bevacizumab |
Non-Small Cell Lung Cancer | Sun Yat-sen University | August 2022 | Phase 2 |
| NCT05380024 | Recruiting | Drug: Ensartinib | Non Small Cell Lung Cancer | Peking University Cancer Hospital & Institute |
August 17, 2022 | Phase 2 |
| NCT05341583 | Recruiting | Drug: Ensartinib Drug: Placebo |
Non-small Cell Lung Cancer | Betta Pharmaceuticals Co., Ltd. |
May 24, 2022 | Phase 3 |
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