| Name | Dovitinib |
| Description | Dovitinib is an orally active, multi-targeted tyrosine kinase (RTK) inhibitor with anti-tumor effects. |
| Cell Research | 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) |
| Kinase Assay | 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. |
| In vitro | METHODS: FGFR3 cell lines (KMS11, KMS18, OPM2, H929) and FGFR3 cell lines were treated with Dovitinib (CHIR-258) (12.5, 25, 50, 100, 200, 300, 400 nM, 48 hours), and cell viability was detected by MTT.
RESULTS Dovitinib inhibited the proliferation of KMS11 (FGFR3-Y373C), OPM2 (FGFR3-K650E), and KMS18 (FGFR3-G384D) cells with IC50 values of 90 nM (KMS11 and OPM2) and 550 nM, respectively. [1] |
| In vivo | METHODS: Dovitinib (CHIR-258) (10, 30, 60 mg/kg, orally, once a day, 21 days) was used to treat tumor xenograft model mice, and the growth of tumors in vivo was observed.
RESULTS Significant anti-tumor effects were observed in all three dovitinib dose groups. The minimum effective dose was 10 mg/kg. The growth inhibition in the 10 mg/kg, 30 mg/kg and 60 mg/kg treatment groups was 48% respectively. , 78.5% and 94%. [1] |
| Storage | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice/Shipping at ambient temperature. |
| Solubility Information | DMSO : 7.14 mg/mL (18.2 mM), Sonication is recommended.
Ethanol : < 1 mg/mL (insoluble or slightly soluble)
10% DMSO+40% PEG300+5% Tween 80+45% Saline : 1 mg/mL (2.55 mM), Sonication is recommended.
H2O : < 1 mg/mL (insoluble or slightly soluble)
|
| Keywords | 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 |
| Inhibitors Related | Gilteritinib | Amlexanox | Sunitinib | Sorafenib | Ferulic Acid | glycine | Regorafenib | Ethyl cinnamate | Formononetin | Chloramphenicol | Pazopanib | Albendazole |
| Related Compound Libraries | Failed Clinical Trials Compound Library | Target-Focused Phenotypic Screening Library | Bioactive Compound Library | Membrane Protein-targeted Compound Library | Kinase Inhibitor Library | Tyrosine Kinase Inhibitor Library | Anti-Cancer Clinical Compound Library | Drug Repurposing Compound Library | Inhibitor Library | Bioactive Compounds Library Max | Anti-Cancer Drug Library | Anti-Cancer Active Compound Library |
United States
