| 名稱 | Dovitinib |
| 描述 | Dovitinib is an orally active, multi-targeted tyrosine kinase (RTK) inhibitor with anti-tumor effects. |
| 細(xì)胞實驗 | Cell viability is assessed by 3-(4,5-dimethylthiazol)-2,5-diphenyl tetrazolium (MTT) dye absorbance. Cells are seeded in 96-well plates at a density of 5 × 103 (B9 cells) or 2 × 104 (MM cell lines) cells per well. Cells are incubated with 30 ng/mL aFGF and 100 μg/mL heparin or 1% IL-6 where indicated and increasing concentrations of Dovitinib. For each concentration of Dovitinib, 10 μL aliquots of drug or DMSO diluted in culture medium is added. For drug combination studies, cells are incubated with 0.5 μM dexamethasone, 100 nM Dovitinib, or both simultaneously where indicated. To evaluate the effect of Dovitinib on growth of MM cells adherent to BMSCs, 104 KMS11 cells are cultured on BMSC-coated 96-well plates in the presence or absence of Dovitinib. Plates are incubated for 48 to 96 hours. For assessment of macrophage colony-stimulating factor (M-CSF)-mediated growth, 5 × 103 M-NFS-60 cells/well are incubated with serial dilutions of Dovitinib with 10 ng/mL M-CSF and without granulocyte-macrophage colony-stimulating factor (GM-CSF). After 72 hours cell viability is determined using Cell Titer-Glo Assay. Each experimental condition is performed in triplicate. (Only for Reference) |
| 激酶實驗 | In vitro kinase assays: The inhibitory concentration of 50% (IC50) values for the inhibition of RTKs by Dovitinib are determined in a time-resolved fluorescence (TRF) or radioactive format, measuring the inhibition by Dovitinib of phosphate transfer to a substrate by the respective enzyme. The kinase domains of FGFR3, FGFR1, PDGFRβ, and VEGFR1-3 are assayed in 50 mM HEPES (N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid), pH 7.0, 2 mM MgCl2, 10 mM MnCl2 1 mM NaF, 1 mM dithiothreitol (DTT), 1 mg/mL bovine serum albumin (BSA), 0.25 μM biotinylated peptide substrate (GGGGQDGKDYIVLPI), and 1 to 30 μM adenosine triphosphate (ATP) depending on the Km for the respective enzyme. ATP concentrations are at or just below Km. For c-KIT and FLT3 reactions the pH is raised to 7.5 with 0.2 to 8 μM ATP in the presence of 0.25 to 1 μM biotinylated peptide substrate (GGLFDDPSYVNVQNL). Reactions are incubated at room temperature for 1 to 4 hours and the phosphorylated peptide captured on streptavidin-coated microtiter plates containing stop reaction buffer (25 mM EDTA [ethylenediaminetetraacetic acid], 50 mM HEPES, pH 7.5). Phosphorylated peptide is measured with the DELFIA TRF system using a Europium-labeled antiphosphotyrosine antibody PT66. The concentration of Dovitinib for IC50 is calculated using nonlinear regression with XL-Fit data analysis software version 4.1 (IDBS). Inhibition of colony-stimulating factor-1 receptor (CSF-1R), PDGFRα, insulin receptor (InsR), and insulin-like growth factor receptor 1 (IGFR1) kinase activity is determined at ATP concentrations close the Km for ATP. |
| 體外活性 | 方法：Dovitinib (CHIR-258)（12.5,25,50,100,200,300,400nM，48小時）處理FGFR3細(xì)胞系（KMS11、KMS18、OPM2、H929）和FGFR3細(xì)胞系，MTT檢測細(xì)胞活力。
結(jié)果：Dovitinib 抑制了 KMS11 (FGFR3-Y373C)、OPM2 (FGFR3-K650E) 和 KMS18 (FGFR3-G384D) 細(xì)胞的增殖，IC50 值分別為 90 nM（KMS11 和 OPM2）和 550 nM。[1] |
| 體內(nèi)活性 | 方法：Dovitinib (CHIR-258) （10，30，60 mg/kg，口服，每天一次，21天）治療腫瘤異種移植的模型小鼠，觀察體內(nèi)腫瘤的生長。
結(jié)果：3個Dovitinib劑量組均觀察到顯著的抗腫瘤作用，最小有效劑量為10 mg/kg，其中10 mg/kg、30 mg/kg 和 60 mg/kg 治療組的生長抑制分別為 48%、78.5% 和 94%。[1] |
| 存儲條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | DMSO : 7.14 mg/mL (18.2 mM), Sonication is recommended.
Ethanol : < 1 mg/mL (insoluble or slightly soluble)
H2O : < 1 mg/mL (insoluble or slightly soluble)
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| 關(guān)鍵字 | Fibroblast growth factor receptor | Fms like tyrosine kinase 3 | Vascular endothelial growth factor receptor | CSF-1 receptor | FGFR | inhibit | CSF-1R | CHIR 258 | CSF1R | VEGFR | OPM2 | KMS18 | RTK | FLT3 | SCFR | Cluster of differentiation antigen 135 | CD135 | colony stimulating factor 1 receptor | CHIR258 | TKI 258 | CD117 | Inhibitor | c-Kit | PDGFR | KMS11 | c-Fms | orally | Dovitinib | Platelet-derived growth factor receptor | TKI-258 |
| 相關(guān)產(chǎn)品 | Imatinib | Amlexanox | Gilteritinib | Ribociclib | Formononetin | Axitinib | Ferulic Acid | Regorafenib | Pazopanib | Nintedanib | Sorafenib | Regorafenib monohydrate |
| 相關(guān)庫 | 經(jīng)典已知活性庫 | 抗癌活性化合物庫 | 已知活性化合物庫 | 膜蛋白靶向化合物庫 | 藥物功能重定位化合物庫 | 酪氨酸激酶分子庫 | 抗癌臨床化合物庫 |