Lenvatinib (E7080)

Lenvatinib (E7080)は一種の多ターゲット阻害剤で、無細胞試験でVEGFR2(KDR)/VEGFR3(Flt-4)に作用する効果が一番強くて、IC50値が4 nM/5.2 nM,になることです。Lenvatinib (E7080)はVEGFR1/Flt-1に作用する効果が少し弱くて、VEGFR2/3に作用する選択性はFGFR1とPDGFRα/βに作用する選択性より10倍左右がそれぞれ高くなります。臨床3期。

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Lenvatinib (E7080) 化学構造
分子量: 426.85

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製品説明

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製品の説明

生物活性

製品説明 Lenvatinib (E7080)は一種の多ターゲット阻害剤で、無細胞試験でVEGFR2(KDR)/VEGFR3(Flt-4)に作用する効果が一番強くて、IC50値が4 nM/5.2 nM,になることです。Lenvatinib (E7080)はVEGFR1/Flt-1に作用する効果が少し弱くて、VEGFR2/3に作用する選択性はFGFR1とPDGFRα/βに作用する選択性より10倍左右がそれぞれ高くなります。臨床3期。
ターゲット 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試験 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試験 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]
臨床試験 E7080 is currently in Phase I clinical trials in patients with Refractory Solid Tumors Lymphomas.
特集

プロトコル (参考用のみ)

キナーゼアッセイ: [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.

細胞アッセイ: [2]

細胞株 HUVECs
濃度 0-10 μM
反応時間 72 hours
実験の流れ 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.

動物実験: [1]

動物モデル H146 tumor cells are implanted subcutaneously (s.c.) into the flank region of female BALB/c nude mice.
製剤 E7080 is dissolved in suspended in 0.5% methylcellulose.
投薬量 ≤100 mg/kg
投与方法 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

参考

化学情報

Download Lenvatinib (E7080) SDF
分子量 426.85
化学式

C21H19ClN4O4

CAS No. 417716-92-8
保管 3年-20℃
2年-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 40 mg/mL warming (93.7 mM)
Water <1 mg/mL
Ethanol <1 mg/mL
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.
化学名 1-(4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-2-chlorophenyl)-3-cyclopropylurea

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