Lenvatinib (E7080)

 

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Biological Activity

Description	E7080 (Lenvatinib) is a multi-target inhibitor, mostly for VEGFR2(KDR)/VEGFR3(Flt-4) with IC50 of 4 nM/5.2 nM, less potent against VEGFR1/Flt-1, ~10-fold more selective for VEGFR2/3 against FGFR1, PDGFRα/β. Phase 3.
Targets	VEGFR2	VEGFR3	VEGFR1	FGFR1	PDGFRα	PDGFRβ
IC50	4 nM	5.2 nM	22 nM [1]	46 nM [1]	51 nM [1]	39 nM [1]
In vitro	E7080, as a potent inhibitor of in vitro angiogenesis, shows a significantly inhibitory effect on VEGF/KDR and SCF/Kit signaling. According to the in vitro receptor tyrosine and serine/threonine kinase assays, E7080 inhibits Flt-1, KDR, Flt-4 with IC50 of 22, 4.0 and 5.2 nM, respectively. In addition to these kinases, E7080 also inhibits FGFR1 and PDGFR tyrosine kinases with IC50 value of 46, 51 and 100 nM for FGFR1, PDGFRα and PDGFRβ, respectively. [1] E7080 potently inhibits phosphorylation of VEGFR2 (IC50, 0.83 nM) and VEGFR3 (IC50, 0.36 nM) in HUVECs which is stimulated by VEGF and VEGF-C, respectively. [2] A recent study shows that E7080 treatment (both at 1 μM and 10 μM) results in a significant inhibition of cell migration and invasion by inhibiting FGFR and PDGFR signaling. [3]
In vivo	When orally administrated in a H146 xenograft model, E7080 inhibits the growth of H146 tumor at 30 and 100 mg/kg in a dose-dependent manner and leads to tumor regression at 100 mg/kg. Furthermore, E7080 at 100 mg/kg decreases microvessel density more than anti-VEGF antibody and imatinib treatment. [1] E7080 significantly inhibits local tumor growth in a MDA-MB-231 mammary fat pad (m.f.p.) model with RTVs (calculated tumor volume on day 8/tumor volume on day 1) of 0.81, and reduces both angiogenesis and lymphangiogenesis of established metastatic nodules of MDA-MB-231 tumor in the lymph nodes. [2]
Features

Protocol(Only for Reference)

Kinase Assay: ^[1]

In vitro kinase assay [1]

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 E7080 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-minute incubation at 30°C, the reaction is stopped by adding 0.5 M EDTA (10 μL/well) to the reaction mixture in each well. Dilution buffer adequate to each kinase assay is added to the reaction mixture. In the HTRF assay, 50 μL of the reaction mixture is transferred to a 96-well 1/2 area black EIA/RIA plate, HTRF solution (50 μL/well) is added to the reaction mixture, and then kinase activity is determined by measurement of fluorescence with a time-resolved fluorescence detector at an excitation wavelength of 337 nm and an emission wavelengths of 620 and 665 nm. In the ELISA, 50 μL of the reaction mixture is incubated in avidin coated 96-well polystyrene plates at room temperature for 30 minutes. After washing with wash buffer, PY20-HRP solution (70 μL/well) is added and the reaction mixture is incubated at room temperature for 30 minutes. After washing with wash buffer, TMB reagent (100 μL/well) is added to each well. After several minutes (10–30 minutes), 1 M H3PO4 (100 μL/well) is added to each well. Kinase activity is determined by measurement of absorbance at 450 nm with a microplate reader.

Cell Assay: ^[2]

Cell lines	HUVECs
Concentrations	0-10 μM
Incubation Time	72 hours
Method	HUVECs (1,000 cells in each well in serum-free medium containing 2% fetal bovine serum) and L6 rat skeletal muscle myoblasts (5,000 cells in each well in serum-free DMEM) are dispensed in a 96-well plate and incubated overnight. E7080 and either VEGF (20 ng/mL) or FGF-2 (20 ng/mL) containing 2% fetal bovine serum and PDGFβ (40 ng/mL) are added to each well. Cells are incubated for 3 days and then the ratios of surviving cells are measured by WST-1 reagent. For proliferation assay, samples are duplicated and three separate experiments are done.

Animal Study: ^[1]

Animal Models	H146 tumor cells are implanted subcutaneously (s.c.) into the flank region of female BALB/c nude mice.
Dosages	≤100 mg/kg
Administration	Administered via p.o.
Solubility	0.5% methylcellulose, 30 mg/mL

1

References

Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number	Recruitment	Conditions	Sponsor /Collaborators	Start Date	Phases
NCT01433991	Recruiting	Advanced Solid Tumors	Eisai Inc.	2011-10	Phase 1|Phase 2
NCT01529112	Active, not recruiting	Non-Small Cell Lung Cancer	Eisai Inc.|PharmaBio Development Inc.	2011-11	Phase 2
NCT01728623	Recruiting	Thyroid Cancer	Eisai Inc.|Eisai Co., Ltd.	2012-08	Phase 2
NCT01761266	Recruiting	Hepatocellular Carcinoma (HCC)	Eisai Inc.|Eisai Limited	2013-02	Phase 3
NCT01877083	Recruiting	KIF5B-RET-Positive Adenocarcinoma of the Lung	Eisai Inc.|Eisai Co., Ltd.	2013-04	Phase 2

Chemical Information

Download Lenvatinib (E7080) SDF

Chemical Name	1-(4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-2-chlorophenyl)-3-cyclopropylurea

Preparing Stock Solutions

Stock Solution (1ml DMSO)	1mM	10mM	20mM	30mM
Mass(mg)	0.42685	4.2685	8.537	12.8055

Customer Reviews (2)

Click to enlarge	Rating
	Source	Chin J Cancer Res. 2013 Oct;25(5):572-84 . Lenvatinib (E7080) purchased from Selleck
	Method	RTCA
	Cell Lines	HT29 cells
	Concentrations	6.25-100 nM
	Incubation Time	12, 24, 36 h
	Results	E7080 treated HT29 cells exhibited decreasing CI values in a concentration-dependent manner. While 100 nmol/L has shown complete cytotoxic effect and decreased CI to 0.1, 50 nmol/L decreased CI to 0.4. Both showed statistically significant cytotoxic effect when compared with the control (P<0.05).

Product Citations (2)

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  Activation of coagulation by lenalidomide-based regimens for the treatment of multiple myeloma. [Isozumi Y, et al. PLoS One 2013;8(5):e64369]

  
  PubMed: 23696885


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  Effects of tyrosine kinase inhibitor E7080 and eNOS inhibitor L-NIO on colorectal cancer alone and in combination. [Altun A, et al. Chin J Cancer Res 2013;25(5):572-84]

  
  PubMed: 24255582