Lenvatinib (E7080)

Modify Date: 2024-01-02 08:42:27

Lenvatinib (E7080) structure	Common Name	Lenvatinib (E7080)
	CAS Number	417716-92-8	Molecular Weight	426.853
	Density	1.5±0.1 g/cm3	Boiling Point	627.2±55.0 °C at 760 mmHg
	Molecular Formula	C₂₁H₁₉ClN₄O₄	Melting Point	N/A
	MSDS	N/A	Flash Point	333.1±31.5 °C

Use of Lenvatinib (E7080)

Lenvatinib is an oral, multi-targeted tyrosine kinase inhibitor with IC50s of 4 and 5.2 nM for VEGFR2(KDR) and VEGFR3(Flt-4), respectively. Lenvatinib is less potent against VEGFR1/Flt-1 and shows approximately 10-fold selectivity for VEGFR2/3 over FGFR1, PDGFRα/β.

Name	lenvatinib
Synonym	More Synonyms

Description	Lenvatinib is an oral, multi-targeted tyrosine kinase inhibitor with IC50s of 4 and 5.2 nM for VEGFR2(KDR) and VEGFR3(Flt-4), respectively. Lenvatinib is less potent against VEGFR1/Flt-1 and shows approximately 10-fold selectivity for VEGFR2/3 over FGFR1, PDGFRα/β.
Related Catalog	Signaling Pathways >> Protein Tyrosine Kinase/RTK >> VEGFR Research Areas >> Cancer
Target	VEGFR2:4 nM (IC50) VEGFR3:5.2 nM (IC50)
In Vitro	Lenvatinib inhibits KIT kinase with an IC50 value of 100 nM. lenvatinib inhibits SCF- and VEGF-induced tube formation in a dose-dependent manner with IC50 values of 5.2 and 5.1 nM, respectively. Lenvatinib inhibits SCF-induced proliferation of another human SCLC, H526 cells, which expresses KIT, at the concentrations required for the inhibition of KIT kinase. The IC50 values of Lenvatinib against phosphorylation of KDR and KIT in HUVEC are about 500 times lower than those against H146 proliferation in vitro[1]. Lenvatinib inhibits both angiogenesis and lymphangiogenesis induced by human breast cancer cells, and significantly inhibits tumor growth of MDA-MB-231. Lenvatinib and bevacizumab treatment decreases MVD by almost the same extent[2]. Lenvatinib inhibits proliferation at high concentrations (mean IC50s 23.6-44.17 μM) in the majority of the cell lines, while the IC50 in the KM12C colon cancer cell line is 9.54 μM[3].
In Vivo	Lenvatinib inhibits the growth of H146 tumor at 30 and 100 mg/kg (BID, QDx21) in a dose-dependent manner and causes tumor regression at 100 mg/kg in H146 xenograft model. IHC analysis with anti-CD31 antibody shows that lenvatinib at 100 mg/kg decreases microvessel density more than anti-VEGF antibody and imatinib treatment[1]. lenvatinib (100 mg/kg, p.o.) is administeredand bevacizumab significantly inhibits local tumor growth at the m.f.p., and at the end of treatment, lenvatinib also significantly inhibits metastasis to both regional lymph nodes and distant lung[2].
Kinase Assay	Tyrosine kinase assays are performed by HTRF (KDR, VEGFR1, FGFR1, c-Met, EGFR) and ELISA (PDGFRβ), using the recombinant kinase domains of receptors. In both assays, 4 μL of serial dilutions of lenvatinib are mixed in a 96-well round plate with 10 μL of enzyme, 16 μL of poly (GT) solution (250 ng) and 10 μL of ATP solution (1 μM ATP) (final concentration of DMSO is 0.1%). In wells for blanks, no enzyme is added. In control wells no test article is added. The kinase reaction is initiated by adding ATP solution to each well. After 30-min incubation at 30°C, the reaction is stopped by adding 0.5mol/LEDTA (10 μL/well) to the reaction mixture in each well. Dilution buffer adequate to each kinase assay is added to the reaction mixture.
Cell Assay	H146 (1.2×103 cells/50 μL/well) in SFM containing 0.5% BSA are cultured in 96-well multi-plates. After overnight culture at 37°C, SFM (150 μL/well) containing 0.5% FBS and several concentrations of SCF are added with or without several concentrations of compound. After culture for 72 hr, the ratios of surviving cells are measured by WST-1.
Animal Admin	Female BALB/c nude mice (8-12 weeks old, 20-25 g) are maintained under clean-room conditions. H146 tumor cells (6.5×106) are implanted subcutaneously (s.c.) into the flank region of mice. Twelve days after inoculation, mice are randomized into control (n=12) and treatment (n=6 or n=5) groups and this point in time is identified as day 1. Lenvatinib and Imatinib, and VEGF neutralization antibody are suspended in 0.5% methylcellulose and saline, respectively, and administered orally twice a day for lenvatinib and imatinib and twice a week for antibody from day 1 to day 21. Tumor volume is measured on the indicated days and calculated. Antitumor activity is shown as a relative tumor volume (RTV=calculated tumor volume at indicated days/volume on day 1).
References	[1]. Matsui J, et al. 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. Int J Cancer. 2008, 122(3), 664-671. [2]. Matsui J, et al. Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin Cancer Res. 2008, 14(17),545 [3]. Glen H, et al. E7080, a multi-targeted tyrosine kinase inhibitor suppresses tumor cell migration and invasion. BMC Cancer. 2011, 11, 309.

Density	1.5±0.1 g/cm3
Boiling Point	627.2±55.0 °C at 760 mmHg
Molecular Formula	C₂₁H₁₉ClN₄O₄
Molecular Weight	426.853
Flash Point	333.1±31.5 °C
Exact Mass	426.109497
PSA	115.57000
LogP	3.39
Vapour Pressure	0.0±1.8 mmHg at 25°C
Index of Refraction	1.697
Storage condition	2-8℃