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Lenvatinib

Cat. No. M1841

Lenvatinib Structure

Synonym: E7080

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10mg USD 130 In stock
50mg USD 500 In stock
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Quality Control
Biological Activity

Lenvatinib (E7080) is an orally active inhibitor of multiple receptor tyrosine kinases including VEGF, FGF and SCF receptors. Lenvatinib was found to be transformed to a GSH conjugate, through displacement of an O-aryl moiety, at the quinoline part of the molecule in the liver and kidneys. The GSH conjugate underwent further hydrolysis by γ-glutamyltranspeptidase and dipeptidases, followed by intramolecular rearrangement, to form N-cysteinyl quinoline derivatives, which were dimerized to form disulfide dimers and also formed an N,S-cysteinyl diquinoline derivative. In urine, a thioacetic acid conjugate of the quinoline was also observed as one of the major metabolites of lenvatinib. Lenvatinib is a 4-O-aryl quinoline derivative, and such compounds have been known to undergo conjugation with GSH, accompanied by release of the O-aryl moiety. Because of intramolecular rearrangement in the case of lenvatinib, hydrolysis of the GSH conjugate yielded N-cysteinylglycine and N-cysteine conjugates instead of the corresponding S-conjugates. Because the N-substituted derivatives possess free sulfhydryl groups, dimerization through disulfide bonds and another nucleophilic substitution reaction with lenvatinib resulted in the formation of disulfanyl dimers and an N,S-cysteinyl diquinoline derivative, respectively. Oral administration of Lenvatinib inhibited tumor growth of H146 cells at doses of 30 and 100 mg/kg in a dose-dependent manner and caused tumor regression at 100 mg/kg. While anti-VEGF antibody also slowed tumor growth, it did not cause tumor regression. These results indicate that KIT signaling has a role in tumor angiogenesis of SCF-producing H146 cells, and Lenvatinib causes regression of H146 tumors as a result of antiangiogenic activity mediated by inhibition of both KIT and VEGF receptor signaling.

Protocol
Cell Experiment
Cell lines H146 cells
Preparation method Proliferation assay
H146 (1.2 3 103 cells/50 lL/well) in SFM containing 0.5% BSA were cultured in 96-well multi-plates. After overnight culture at 37℃, SFM (150 lL/well) containing 0.5% FBS and several concentrations of SCF were added with or without several concentrations of compound. After culture for 72 hr, the ratios of surviving cells were measured by WST-1.
Concentrations 0~10 μM
Incubation time 72 hr
Animal Experiment
Animal models Female BALB/c nude mice H146 cells tumor xenograft model
Formulation 0.5% methylcellulose
Dosages 30, 100mg/kg twice a day from day 1 to day 21
Administration orally
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
Species Mouse Rat Rabbit Guinea pig Hamster Dog
Weight (kg) 0.02 0.15 1.8 0.4 0.08 10
Body Surface Area (m2) 0.007 0.025 0.15 0.05 0.02 0.5
Km factor 3 6 12 8 5 20
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Chemical Information
Molecular Weight 426.85
Formula C21H19ClN4O4
CAS Number 417716-92-8
Purity 100.00%
Solubility DMSO
Storage at -20°C
References

A phase I study of E7080, a multitargeted tyrosine kinase inhibitor, in patients with advanced solid tumours.
Boss et al. Br J Cancer. 2012 May 8;106(10):1598-604. PMID: 22516948.

Development and validation of LC-MS/MS assays for the quantification of E7080 and metabolites in various human biological matrices.
Dubbelman et al. J Chromatogr B Analyt Technol Biomed Life Sci. 2012 Mar 1;887-888:25-34. PMID: 22309776.

Unique metabolic pathway of [(14)C]lenvatinib after oral administration to male cynomolgus monkey.
Inoue et al. Drug Metab Dispos. 2012 Apr;40(4):662-70. PMID: 22207053.

E7080, a multi-targeted tyrosine kinase inhibitor suppresses tumor cell migration and invasion.
Glen et al. BMC Cancer. 2011 Jul 22;11:309. PMID: 21781317.

E7080 suppresses hematogenous multiple organ metastases of lung cancer cells with nonmutated epidermal growth factor receptor.
Ogino et al. Mol Cancer Ther. 2011 Jul;10(7):1218-28. PMID: 21551260.

E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition.
Matsui J, et al. Int J Cancer. 2008 Feb 1;122(3):664-71. PMID: 17943726.

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  Catalog
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Keywords: Lenvatinib, E7080 supplier, VEGFR/PDGFR, inhibitors

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