Lenvatinib (E7080) is an orally active inhibitor of multiple receptor tyrosine kinases including VEGF, FGF and SCF receptors. Lenvatinib (E7080) has IC50s of 4, 5.2, 22 nM for VEGFR2 (KDR), VEGFR3 (Flt-4), and VEGFR1 (Flt-1), respectively. Lenvatinib inhibits PDGFRα, PDGFRβ, FGFR1, and KIT with IC50s of 51, 39, 46, and 100 nM, respectively. 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.
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.
J Virol. 2020 Feb 14;94(5):e01791-19.
|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.
|Incubation time||72 hr|
|Animal models||Female BALB/c nude mice H146 cells tumor xenograft model|
|Dosages||30, 100mg/kg twice a day from day 1 to day 21|
|Solubility (25°C)||DMSO 12 mg/mL|
Powder -20°C 3 years ; 4°C 2 years
In solvent -80°C 6 months ; -20°C 1 month
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
 Matsui J, et al. Int J Cancer. 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.
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