Lenvatinib (E7080)

Lenvatinib (E7080) 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 in cell-free assays. Phase 3.

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Lenvatinib (E7080) Chemical Structure

Lenvatinib (E7080) Chemical Structure
Molecular Weight: 426.85

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Customer Product Validation(3)

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Product Description

Biological Activity

Description Lenvatinib (E7080) 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 in cell-free assays. Phase 3.
Targets VEGFR2/KDR [1]
(Cell-free assay)
VEGFR3/FLT4 [1]
(Cell-free assay)
VEGFR1/FLT1 [1]
(Cell-free assay)
PDGFRβ [1]
(Cell-free assay)

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IC50 4.0 nM 5.2 nM 22 nM 39 nM
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.
Formulation E7080 is dissolved in suspended in 0.5% methylcellulose.
Dosages ≤100 mg/kg
Administration Administered via p.o.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
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.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Matsui J, et al. Int J Cancer. 2008, 122(3), 664-671.

[2] Matsui J, et al. Clin Cancer Res. 2008, 14(17),5459-5465.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2015-05-23)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02430714 Not yet recruiting Thyroid Neoplasms Eisai Co., Ltd.|Eisai Inc. May 2015 --
NCT02430714 Not yet recruiting Thyroid Neoplasms Eisai Co., Ltd.|Eisai Inc. May 2015 --
NCT02432274 Recruiting Tumors|Relapsed or Refractory Solid Malignant Tumors|Osteosarcoma|Differentiated Thyroid Cancer (DTC) Eisai Limited|Eisai Inc. December 2014 Phase 1|Phase 2
NCT02432274 Recruiting Tumors|Relapsed or Refractory Solid Malignant Tumors|Osteosarcoma|Differentiated Thyroid Cancer (DTC) Eisai Limited|Eisai Inc. December 2014 Phase 1|Phase 2
NCT01877083 Recruiting KIF5B-RET-Positive Adenocarcinoma of the Lung Eisai Co., Ltd.|Eisai Inc. April 2013 Phase 2

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Chemical Information

Download Lenvatinib (E7080) SDF
Molecular Weight (MW) 426.85
Formula

C21H19ClN4O4

CAS No. 417716-92-8
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 40 mg/mL (93.7 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 0.5% methylcellulose 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 1-(4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-2-chlorophenyl)-3-cyclopropylurea

Research Area

Customer Product Validation (3)


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Rating
Source Asian Pac J Cancer Prev 2014 15(7), 3113-21. Lenvatinib (E7080) purchased from Selleck
Method Annexin V-FITC assay
Cell Lines HT29 cells
Concentrations 12.5, 25, 50 nM
Incubation Time
Results The apoptosis induction was assessed by Annexin V-FITC assay. In the dot plot of flow cytometric analysis, the lower-right (LR) area was the Annexin V positive/PI negative portion which represented the preapoptotic fraction, the upper-right (UR) area was the Annexin V positive/PI positive portion which represented the apoptotic fraction. The agents DuP-697 +E7080 combinations at 50+50, 25+25 and 12.5+12.5 nM showed strong concentration dependent apoptotic effect. The percentage of UR (apoptosis portion) area was 78.4%, 67.3% and 33.4% respectively.

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Rating
Source Chin J Cancer Res 2013 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).

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Rating
Source Chin J Cancer Res 2013 25(5), 572-84. Lenvatinib (E7080) purchased from Selleck
Method RTCA
Cell Lines HT29 cells
Concentrations
Incubation Time 24 h
Results Twenty-four hours after treatment with E7080, the IC50 of 5.60×10-8 mol/L was achieved. Calculation of IC50 of E7080 (IC50 =5.60×10–8 mol/L, square R =0.998).

Product Use Citation (3)

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