| 名稱 | PF-04217903 |
| 描述 | MET Tyrosine Kinase Inhibitor PF-04217903 is an orally bioavailabe, small-molecule tyrosine kinase inhibitor with potential antineoplastic activity. |
| 細(xì)胞實(shí)驗(yàn) | Cells are treated with different concentrations PF-04217903 for 4 days. Cell proliferation is assessed by counting content of each well using a Coulter counter machine.(Only for Reference) |
| 激酶實(shí)驗(yàn) | Cellular c-Met phosphorylation ELISA: A549 cells with endogenous human WT c-Met are seeded in 96-well plates in growth medium and cultured overnight. On the second day of the assay, the growth medium is replaced with serum-free medium (with 0.04% BSA). Serial dilutions of PF-04217903 are added to each well, and cells are incubated at 37 °C for 1 hour. Then 40 ng/mL HGF is added to the cells for 20 minutes. The cells are washed once with HBSS supplemented with 1 mM Na3VO4, and protein lysates are generated from cells using lysis buffer. Phosphorylation of c-Met is assessed by an ELISA method utilizing capture antibodies specific for c-Met and a detection antibody specific for phosphorylated tyrosine residues. Antibody-coated plates are incubated in the presence of protein lysates at 4 °C overnight and washed with 1% Tween 20 in PBS seven times. HRP-PY20 (horseradish peroxidase-conjugated anti-phosphotyrosine) is diluted 1:500 in blocking buffer and added to each plate for 30 minutes. Plates are then washed again, and TMB peroxidase substrate is added to initiate the HRP-dependent colorimetric reaction and the reaction stopped by addition of 0.09 N H2SO4. ELISA end points are the absorbance measured at 450 nm using a spectrophotometer. IC50 value is calculated by concentration-response curve fitting utilizing a Microsoft Excel-based four-parameter analytical met |
| 體外活性 | 盡管在舒尼替尼敏感的B16F1和Tib6腫瘤模型中不能抑制腫瘤生長(zhǎng),但與單獨(dú)使用舒尼替尼或PF-04217903相比,PF-04217903和舒尼替尼聯(lián)用顯著抑制舒尼替尼耐受性EL4和LLC腫瘤模型的腫瘤生長(zhǎng),血管擴(kuò)張,表明舒尼替尼耐藥腫瘤中HGF/c-Met軸的功能作用. |
| 體內(nèi)活性 | PF-04217903明顯抑制 LXFA 526L和LXFA 1647L克隆生長(zhǎng),IC50分別為16 nM和13 nM,與西妥昔單抗聯(lián)用效果增強(qiáng)。PF-04217903有效抑制c-Met驅(qū)動(dòng)的生物過程,如多種腫瘤細(xì)胞的生長(zhǎng),運(yùn)動(dòng),侵襲和形態(tài)學(xué)變化。2 μM PF-04217903促進(jìn)GTL-16 細(xì)胞死亡,其涉及磷酸化的4E-BP1,ERK/MAPK相關(guān)蛋白和 PI3K/AKT通路的下調(diào)。PF-04217903選擇性比十字孢堿或PF-02341066高,PF-04217903作用于c-Met選擇性比作用于其他一組208種激酶選擇性高1000多倍,對(duì)c-Met致癌突變更敏感。除WT c-Met之外,PF-04217903顯示出類似的抑制c-Met-H1094R,c-Met-R988C和c-Met-T1010I活性的效力,IC50為3.1 nM,6.4 nM和6.7 nM,但對(duì)c-Met-Y1230C沒有抑制活性,IC50>10 μM。PF-04217903和舒尼替尼聯(lián)用明顯抑制內(nèi)皮細(xì)胞增殖,但是不抑制腫瘤細(xì)胞B16F1,Tib6,EL4和LLC。 |
| 存儲(chǔ)條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | DMSO : 20 mg/mL (53.71 mM), Sonication is recommended.
Ethanol : < 1 mg/mL (insoluble or slightly soluble)
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| 關(guān)鍵字 | lung | migration | gastric | GTL-16 | PF-04217903 | c-Met/HGFR | inhibit | phosphorylation | colon | PF 04217903 | phospho-PDGFRβ | PF04217903 | carcinoma | Inhibitor |
| 相關(guān)產(chǎn)品 | Capmatinib 2HCl | Cabozantinib S-malate | Crizotinib | Amuvatinib | BMS 777607 | (±)-Norcantharidin | Capmatinib xHCl | LMTK3-IN-1 | L-Ascorbic acid 2-phosphate trisodium | Norcantharidin | Bacitracin Zinc | AMG-458 |
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