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| ln Vitro |
Zotatifin causes the stable ternary complex [eIF4A-RNA-eFT226] to form. In the presence or absence of eFT226, ozotifin lengthens the residence duration of eIF4A1 bound to the AGAGAG RNA surface, with Kd values of 0.021 μM and 8.0 μM [1]. has sequence-dependent inhibition of in vitro translation, with IC50 values in the MDA-MB-231 cell line of 1.5 nM, 13.8 nM, 92.5 nM, and 217.5 nM. temporarily transfected with 5'-UTRs for AGAGAG, GGCGGC, CCGCCG, and CAACAA. In a dose-dependent manner, zotatifin (0.0001 μM-1 μM; 72 hours) suppresses the development of tumor cells. It exhibits strong anti-apoptotic action in MDA-MB-231 tumor cells (GI50<15 nM). Zotatifin (0.0001 μM-1 μM; 72 hours) suppresses the proliferation of tumor cells against TMD8, SU-DHL-2, HBL1, Pfeiffer, and SU-DHL-; however, the anti-proliferative action of eFT226 is abruptly relieved by eIF4A1 F163L [1]. GI50 value 6, SU-DHL-10, VAL, Carnaval, U2973, Ramos, Jeko1, Mino, and Rec-1 cells have the following performance values: 4.1 nM, 3 nM, 5.6 nM, 3.7 nM, 5.3 nM, 7.3 nM, and 6.6 nM, in that order. The transformation regulatory protein of coconut genes is induced by zotatifin (30 μM-100 μM; 3 or 24 hours) in a dose- and time-dependent manner. Zotatifin's antiviral efficacy is evaluated using a number of certified tests, including the TCID50 assay, plaque assay, NP-staining assay, and others [2]. Less viral NP protein and less concentration were found in Vero E6 cells infected with SARS-CoV-2 isolates at concentrations of 100 nM, 200 nM, 500 nM, 2 μM, and 10 μM; 1 or 2 hours prior to virus isolation.
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| ln Vivo |
In TMD8 xenografts, HBL1-bearing xenografts, Pfeiffer-bearing xenografts, and SU-DHL-6-bearing xenografts, zogafitin (IV; 1 mg/kg; 14–22 days) decreases tumor size and inhibits plaques. The percentages of tumor growth in SU-DHL-10 xenograft- and Ramos-bearing animals were 97%, 87%, 70%, 83%, 37%, and 75%, respectively [1]. In B-cell-localized xenograft models, zogafitin (IV; 0.001 mg/kg-1 mg/kg; 15 days) is well tolerated and reduces the growth of B-cell-localized xenografts [1].
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| Cell Assay |
Cell viability assay [1]
Cell Types: MDA-MB-231 tumor cell Tested Concentrations: 0.0001μM, 0.001μM, 0.01μM, 0.1μM, 1μM Incubation Duration: 72 hrs (hours) Experimental Results: Inhibition of viral infectivity of cells [2]. The F163L mutant rescued the antiproliferative effect of growth with a GI50 of 15 nM. Cell proliferation assay[1] Cell Types: DLBCL-ABC; DLBCL-GCB; Burkitt; and MCL Tumor Type Cell Tested Concentrations: 0.0001 μM, 0.001 μM, 0.01 μM, 0.1 μM, 1 μM Incubation Duration: 72 hrs (hours) Experimental Results: Inhibition Cell growth, GI50 values range from 3 nM to 20 nM. Cell proliferation experiment [1] Cell Types: TMD8 and Pfeiffer DLBCL Tumor cell Tested Concentrations: 30 μM; 100 μM Incubation Duration: 3 or 24 hrs (hours) Experimental Results: MYC, CCND3, Bcl2 and MCL1 protein levels were diminished. |
| Animal Protocol |
Animal/Disease Models: B-cell lymphoma xenograft model [1]
Doses: 0.001 mg/kg; 0.1 mg/kg; 1 mg/kg Route of Administration: intravenous (iv) (iv)injection; 15-day Experimental Results: In B-cell lymphoma xenograft model Show efficacy. |
| References | |
| Additional Infomation |
Zotatifin is under investigation in clinical trial NCT04092673 (Study of Eft226 in Subjects With Selected Advanced Solid Tumor Malignancies).
Zotatifin is a selective inhibitor of the eukaryotic translation initiation factor 4A (eIF4A), with potential antineoplastic activity. Upon administration of zotatifin, this agent targets and binds to elF4A, and promotes eIF4A binding to mRNA with specific polypurine motifs within their 5'-untranslated region (5'-UTR), leading to the formation of a stable sequence-specific ternary complex with eIF4A and mRNA (elF4A- zotatifin-mRNA). This results in the translational repression of key oncogenes and anti-apoptotic proteins involved in tumor cell proliferation, survival and metastasis, such as KRAS, Myc, myeloid cell leukemia-1 (Mcl-1), B-cell lymphoma 2 (Bcl-2), cyclin-dependent kinase (CDK) 4 and 6, cyclin D, fibroblast growth factor receptor (FGFR) 1 and 2, human epidermal growth factor receptor 2 (HER2; ERBB2), and beta-catenin. The inhibition of the expression of these oncogenes leads to the inhibition of various oncogenic signal transduction pathways. This inhibits proliferation and induces apoptosis in tumor cells. eIF4A, a RNA helicase and the rate-limiting component of the eukaryotic translation initiation complex, catalyzes the ATP-dependent unwinding of RNA duplexes and facilitates 43S ribosome scanning within the 5'-UTR. elF4A is activated by various oncogenic signaling pathways, including RAS/mitogen-activated protein kinase (MAPK) and phosphatidylinositide 3-kinase (PI3K)/AKT pathways, and regulates the translation of oncogenes and tumor survival factors with complex secondary structures within the 5'-UTRs that are required for tumor cell proliferation, survival and metastasis. |
| Molecular Formula |
C28H29N3O5
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| Molecular Weight |
487.5470
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| Exact Mass |
487.21
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| CAS # |
2098191-53-6
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| Related CAS # |
rel-Zotatifin;2098191-54-7
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| PubChem CID |
129138801
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| Appearance |
White to off-white solid powder
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| LogP |
2.4
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
36
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| Complexity |
819
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| Defined Atom Stereocenter Count |
5
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| SMILES |
O1C2=C([H])C(=NC(=C2[C@@]2([C@@]([H])([C@]([H])(C([H])([H])N(C([H])([H])[H])C([H])([H])[H])[C@@]([H])(C3C([H])=C([H])C([H])=C([H])C=3[H])[C@]12C1C([H])=C([H])C(C#N)=C([H])C=1[H])O[H])O[H])OC([H])([H])[H])OC([H])([H])[H]
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| InChi Key |
QYCXWOACFWMQFO-WZWZCULESA-N
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| InChi Code |
InChI=1S/C28H29N3O5/c1-31(2)16-20-23(18-8-6-5-7-9-18)28(19-12-10-17(15-29)11-13-19)27(33,25(20)32)24-21(36-28)14-22(34-3)30-26(24)35-4/h5-14,20,23,25,32-33H,16H2,1-4H3/t20-,23-,25-,27+,28+/m1/s1
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| Chemical Name |
4-[(2S,3R,4S,5S,6R)-4-[(dimethylamino)methyl]-2,3-dihydroxy-10,12-dimethoxy-5-phenyl-7-oxa-11-azatricyclo[6.4.0.02,6]dodeca-1(12),8,10-trien-6-yl]benzonitrile
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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 : ~200 mg/mL (~410.21 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5 mg/mL (10.26 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 (10.26 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 50.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0511 mL | 10.2554 mL | 20.5107 mL | |
| 5 mM | 0.4102 mL | 2.0511 mL | 4.1021 mL | |
| 10 mM | 0.2051 mL | 1.0255 mL | 2.0511 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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