| 名称 | Dovitinib |
| 描述 | Dovitinib is an orally active, multi-targeted tyrosine kinase (RTK) inhibitor with anti-tumor effects. |
| 细胞实验 | 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) |
| 激酶实验 | 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. |
| 体外活性 | 方法：Dovitinib (CHIR-258)（12.5,25,50,100,200,300,400nM，48小时）处理FGFR3细胞系（KMS11、KMS18、OPM2、H929）和FGFR3细胞系，MTT检测细胞活力。
结果：Dovitinib 抑制了 KMS11 (FGFR3-Y373C)、OPM2 (FGFR3-K650E) 和 KMS18 (FGFR3-G384D) 细胞的增殖，IC50 值分别为 90 nM（KMS11 和 OPM2）和 550 nM。[1] |
| 体内活性 | 方法：Dovitinib (CHIR-258) （10，30，60 mg/kg，口服，每天一次，21天）治疗肿瘤异种移植的模型小鼠，观察体内肿瘤的生长。
结果：3个Dovitinib剂量组均观察到显著的抗肿瘤作用，最小有效剂量为10 mg/kg，其中10 mg/kg、30 mg/kg 和 60 mg/kg 治疗组的生长抑制分别为 48%、78.5% 和 94%。[1] |
| 存储条件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice/Shipping at ambient temperature. |
| 溶解度 | 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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| 关键字 | VEGFR3/FLT4 | VEGFR | Vascular endothelial growth factor receptor | TKI-258 | TKI 258 | SCFR | RTK | Platelet-derived growth factor receptor | PDGFR | orally | OPM2 | KMS18 | KMS11 | Inhibitor | inhibit | Fms like tyrosine kinase 3 | FLT3 | Fibroblast growth factor receptor | FGFR3 | FGFR1 | FGFR | Dovitinib | CSF-1R | CSF1R | CSF-1 receptor | colony stimulating factor 1 receptor | Cluster of differentiation antigen 135 | c-Kit | cKit | CHIR258 | CHIR 258 | c-Fms | CD135 | CD117 |
| 相关产品 | Imatinib | Amlexanox | Gilteritinib | Ribociclib | Formononetin | Axitinib | Ferulic Acid | Regorafenib | Pazopanib | Nintedanib | Sorafenib | Regorafenib monohydrate |
| 相关库 | 抑制剂库 | 经典已知活性库 | 抗癌活性化合物库 | 已知活性化合物库 | 临床失败化合物库 | 激酶抑制剂库 | 临床前化合物库 | 膜蛋白靶向化合物库 | 酪氨酸激酶分子库 | 药物功能重定位化合物库 | 抗癌临床化合物库 | 抗癌药物库 |