| 名稱 | Golvatinib |
| 描述 | Golvatinib (E-7050) is an orally bioavailable dual kinase inhibitor of c-Met (hepatocyte growth factor receptor) and VEGFR-2 (vascular endothelial growth factor receptor-2) tyrosine kinases with potential antineoplastic activity. c-Met/VEGFR kinase inhibitor E7050 binds to and inhibits the activities of both c-Met and VEGFR-2, which may inhibit tumor cell growth and survival of tumor cells that overexpress these receptor tyrosine kinases. c-Met and VEGFR-2 are upregulated in a variety of tumor cell types and play important roles in tumor cell growth, migration and angiogenesis. |
| 細(xì)胞實驗 | Cells (1–3 × 103 cells/100 μL/well) are seeded on 96-well culture plates with various concentrations of E7050 and cultured for 3 days. Then, 10 μL of WST-8 reagent is added to each well, and absorbance is measured at 450 nm compared with a reference measurement at 660 nm using a MTP-500 microplate reader. HUVEC (2 × 103 cells/well) are cultured for 3 days in medium containing HGF (30 ng/mL), VEGF (20 ng/mL), or basic fibroblast growth factor (bFGF) (20 ng/mL) together with serially diluted E7050.(Only for Reference) |
| 激酶實驗 | Western blot analysis: The phosphorylation status of c-Met and VEGFR-2 is detected by Western blot analysis. For c-Met, MKN45 cells are incubated with a serial dilution of E7050 in complete medium at 37 °C for 2 h. For VEGFR-2, HUVEC are starved with human endothelial serum free medium containing 0.5% FBS for 24 h. Subsequently HUVEC are incubated with a serial dilution of E7050 for 1 h and then incubated with 20 ng/mL of human VEGF for 5 min. Cells are lysed by lysis buffer (50 mM HEPES [pH 7.4], 150 mM NaCl, 10% glycerol, 1% Triton X-100, 1.5 mM MgCl2, 1 mM EDTA [pH 8.0], 100 mM NaF, 1 mM phenylmethylsulfonyl fluoride 1 mM sodium orthovanadate, 10 μg/mL aprotinin, 50 μg/mL leupeptin, and 1 μg/mL pepstatin A). The resected tumor samples are homogenized with lysis buffer containing 25 mM β-glycerophosphate and 0.5% (v/v) phosphatase inhibitor cocktail 2 at 4 °C. Cellular debris is removed by centrifugation at 17 860 g for 20 min at 4 °C. Aliquots of the supernatants containing 5-20 μg of protein are subjected to SDS-PAGE under reducing conditions. The proteins are then transferred onto PVDF membranes, blocked with TBS containing 0.05% Tween-20 and either 5% skim milk or 5% BSA. The membranes are probed with the following antibodies: anti-c-Met polyclonal antibody (C-28) and anti-VEGFR-2 polyclonal antibody (C-20); mouse anti-phosphotyrosine clone 4 g10; and anti-VEGFR-2 polyclonal antibody, anti-phospho-VEGFR-2 (Tyr996) polyclonal antibody, and anti-phospho-c-Met (Tyr1234/1235) polyclonal antibody. Detection is performed using a Super Signal enhanced chemiluminescence kit. Immunoreactive bands are visualized by chemiluminescence with an Image Master-VDS-CL detection system. The intensity of each band is measured by using an image analyzer. |
| 體外活性 | 體外研究表明，Golvatinib 強效抑制 c-Met 和 VEGFR-2 的磷酸化作用。Golvatinib 同時也強效抑制了經(jīng) HGF 或 VEGF 刺激的 c-met 擴增腫瘤細(xì)胞和內(nèi)皮細(xì)胞的生長。[1] Golvatinib 通過在體外阻斷 Met/Gab1/PI3K/Akt 途徑，克服了由外源和/或內(nèi)源 HGF 引發(fā)的，對所有可逆的、不可逆的及突變選擇性的 EGFR-TKIs 耐藥性 EGFR 突變型肺癌細(xì)胞系的抵抗。Golvatinib 還能阻止因持續(xù)暴露于 HGF 而誘導(dǎo)的 gefitinib 抵抗性 HCC827 細(xì)胞的出現(xiàn)。[2] |
| 體內(nèi)活性 | 在體內(nèi)研究中，使用Golvatinib展示了對腫瘤中c-Met與VEGFR-2磷酸化的抑制，以及異種移植模型中腫瘤生長和腫瘤血管生成的顯著抑制。對含有c-met擴增的某些腫瘤細(xì)胞系用高劑量Golvatinib（50-200 mg/kg）處理，可誘導(dǎo)腫瘤退縮和消失。在腹膜播散模型中，Golvatinib對腹膜腫瘤顯示出抗腫瘤效果，并顯著延長了受治療小鼠的壽命。[1] 另一項異種移植模型研究中，由HGF轉(zhuǎn)染的Ma-1（Ma-1/HGF）細(xì)胞產(chǎn)生的腫瘤比載體對照腫瘤更易于血管生成，并表現(xiàn)出對ZD1839的抗性。Golvatinib單獨應(yīng)用可抑制血管生成并延緩Ma-1/HGF腫瘤的生長。Golvatinib與ZD1839聯(lián)合使用可顯著抑制腫瘤生長。[3] |
| 存儲條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year
Shipping with blue ice/Shipping at ambient temperature. |
| 溶解度 | H2O : < 1 mg/mL (insoluble or slightly soluble)
10% DMSO+40% PEG300+5% Tween 80+45% Saline : 4 mg/mL (6.31 mM), Sonication is recommended.
Ethanol : < 1 mg/mL (insoluble or slightly soluble)
DMSO : 100 mg/mL (157.81 mM)
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| 關(guān)鍵字 | VEGFR2 | VEGFR | Vascular endothelial growth factor receptor | Inhibitor | inhibit | HGFR | Golvatinib | E7050 | E 7050 | c-Met/HGFR | cMet/HGFR | c-Met | cMet |
| 相關(guān)產(chǎn)品 | glycine | Ribociclib | Lenvatinib | Afatinib | Chloramphenicol | Thymoquinone | Regorafenib | Pazopanib | Sorafenib | Decanoic Acid | Nintedanib esylate | Bacitracin Zinc |
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