| 名稱 | Cabozantinib |
| 描述 | Cabozantinib (XL184) is a multi-targeted tyrosine kinase receptor inhibitor that inhibits VEGFR2, c-Met, Kit, Axl, and Flt3 (IC50=0.035/1.3/4.6/7/11.3 nM). Cabozantinib exhibits both antitumor and antiangiogenic activity. |
| 細(xì)胞實驗 | Receptor phosphorylation of MET, VEGFR2, AXL, FLT3, and KIT were, respectively, assessed in PC3, HUVEC, MDA-MB-231, FLT3-transfected BaF3, and KIT-transfected MDA-MB-231 cells. Cells were serum starved for 3 to 24 hours, then incubated for 1 to 3 hours in serum-free medium with serially diluted cabozantinib before 10-minute stimulation with ligand: HGF (100 ng/mL), VEGF (20 ng/mL), SCF (100 ng/mL), or ANG1 (300 ng/mL). Receptor phosphorylation was determined either by ELISA using specific capture antibodies and quantitation of total phosphotyrosine or immunoprecipitation and Western blotting with specific antibodies and quantitation of total phosphotyrosine. Total protein served as loading controls [1]. |
| 激酶實驗 | The inhibition profile of cabozantinib against a broad panel of 270 human kinases was determined using luciferase-coupled chemiluminescence, 33P-phosphoryl transfer, or AlphaScreen technology. Recombinant human full-length, glutathione S-transferase tag or histidine tag fusion proteins were used, and half maximal inhibitory concentration (IC50) values were determined by measuring phosphorylation of peptide substrate poly(Glu, Tyr) at ATP concentrations at or below the Km for each respective kinase. The mechanism of kinase inhibition was evaluated using the AlphaScreen Assay by determining the IC50 values over a range of ATP concentrations [1]. |
| 動物實驗 | Female nu/nu mice were housed according to the Exelixis Institutional Animal Care and Use Committee guidelines. H441 cells (3 × 10^6) were implanted intradermally into the hind flank and when tumors reached approximately 150 mg, tumor weight was calculated using the formula: (tumor volume = length (mm) × width^2 (mm^2)]/2, mice were randomized (n = 5 per group) and orally administered a single 100 mg/kg dose of cabozantinib or vehicle. Tumors were collected at the indicated time points. Pooled tumor lysates were subjected to immunoprecipitation with anti-MET and Western blotting with anti-phosphotyrosine MET. After blot stripping, total MET was quantitated as a loading control. In a separate experiment, naive mice (n = 5 per group) were administered a single 100 mg/kg dose of cabozantinib or vehicle, followed by intravenous administration of HGF (10 μg per mouse) 10 minutes before liver collection. Analysis of MET phosphorylation in liver lysates was as described above. In a separate experiment, naive mice (n = 5 per group) were administered a single 100 mg/kg dose of cabozantinib or vehicle, followed by intravenous administration of VEGF (10 μg per mouse) 30 minutes before lung collection. Pooled lung lysates were subjected to immunoprecipitation with FLK1 and Western blotting with anti-phosphotyrosine. After blot stripping, total FLK1 was quantitated as a loading control [1]. |
| 體外活性 | 方法：前列腺癌細(xì)胞 LNCaP、C4-2B 和 PC-3 用 Cabozantinib (0.01-5 μM) 處理 72 h，使用 WST-1 Assay 檢測細(xì)胞活力。
結(jié)果：Cabozantinib 以劑量依賴的方式抑制 LNCaP、C4-2B 和 PC-3 細(xì)胞系的細(xì)胞活力。[1]
方法：人腎癌細(xì)胞 786-O 和 A498 用 Cabozantinib (10-100 nM) 處理 1 h，隨后用 HGF (1 nM) 刺激 20 min，使用 Western Blot 檢測靶點蛋白表達(dá)水平。
結(jié)果：10 nM Cabozantinib 處理抑制了 HGF 激活的 pMET、pAKT、pERK 和 p-mTOR。[2] |
| 體內(nèi)活性 | 方法：為檢測體內(nèi)抗腫瘤活性，將 Cabozantinib (60 mg/kg) 口服給藥給脛骨內(nèi)注射前列腺癌細(xì)胞 Ace-1 的 SCID 小鼠，每天一次，持續(xù)五周。
結(jié)果：Cabozantinib 抑制 Ace-1 細(xì)胞在體內(nèi)的進(jìn)展。[1]
方法：為檢測體內(nèi)抗腫瘤活性，將 Cabozantinib (1-60 mg/kg) 口服給藥給攜帶腫瘤 MDA-MB-231、H441 或 C6 的 nu/nu 小鼠，每天一次，持續(xù) 12-14 天。
結(jié)果：Cabozantinib 以劑量依賴的方式抑制腫瘤生長。[3] |
| 存儲條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | H2O : < 1 mg/mL (insoluble or slightly soluble)
DMSO : 50 mg/mL (99.7 mM)
10% DMSO+40% PEG300+5% Tween 80+45% Saline : 9.3 mg/mL (18.54 mM), Suspension. Please add co-solvents sequentially, clarifying the solution as much as possible before adding the next one. Dissolve by heating and/or sonication if necessary. Working solution is recommended to be prepared and used immediately.
Ethanol : < 1 mg/mL (insoluble or slightly soluble)
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| 關(guān)鍵字 | CD135 | angiogenesis | c-Kit | TAM Receptor | CD117 | Tyro3 | HT1080 | Fms like tyrosine kinase 3 | Inhibitor | Axl | A431 | VEGFR | antiangiogenic | FLT3 | c-Met/HGFR | BMS 907351 | B16F10 cells | SCFR | Apoptosis | inhibit | BMS907351 | XL-184 | Cabozantinib | Vascular endothelial growth factor receptor | Cluster of differentiation antigen 135 | XL 184 | Mer |
| 相關(guān)產(chǎn)品 | L-Glutamic acid | Metronidazole | 5-Fluorouracil | Dextran sulfate sodium salt (MW 4500-5500) | Stavudine | Tributyrin | Myricetin | Sorafenib | L-Ascorbic acid | Acetylcysteine | Salicylic acid | Sodium 4-phenylbutyrate |
| 相關(guān)庫 | 經(jīng)典已知活性庫 | 抗癌活性化合物庫 | 抗癌上市藥物庫 | 已知活性化合物庫 | EMA 上市藥物庫 | 膜蛋白靶向化合物庫 | 酪氨酸激酶分子庫 | 抗癌臨床化合物庫 |