Dovitinib (TKI-258, CHIR-258)

Dovitinib (TKI258, CHIR258) is a multitargeted RTK inhibitor, mostly for class III (FLT3/c-Kit) with IC50 of 1 nM/2 nM, also potent to class IV (FGFR1/3) and class V (VEGFR1-4) RTKs with IC50 of 8-13 nM, less potent to InsR, EGFR, c-Met, EphA2, Tie2, IGF-1R and HER2. Phase 4.

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Dovitinib (TKI-258, CHIR-258) Chemical Structure

Dovitinib (TKI-258, CHIR-258) Chemical Structure
Molecular Weight: 392.43

Validation & Quality Control

Customer Reviews(7)

Quality Control & MSDS

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Product Information

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  • Research Area
  • Combination Therapy
    Combination Therapy

Product Description

Biological Activity

Description Dovitinib (TKI258, CHIR258) is a multitargeted RTK inhibitor, mostly for class III (FLT3/c-Kit) with IC50 of 1 nM/2 nM, also potent to class IV (FGFR1/3) and class V (VEGFR1-4) RTKs with IC50 of 8-13 nM, less potent to InsR, EGFR, c-Met, EphA2, Tie2, IGF-1R and HER2. Phase 4.
Targets FLT3 [1] c-Kit [1] FGFR1 [1] VEGFR3/FLT4 [1] FGFR3 [1]

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IC50 1 nM 2 nM 8 nM 8 nM 9 nM
In vitro Dovitinib potently inhibits the FGF-stimulated growth of WT and F384L-FGFR3-expressing B9 cells with IC50 of 25 nM. In addition, Dovitinib inhibits proliferation of B9 cells expressing each of the various activated mutants of FGFR3. Interestingly, there are minimal observed differences in the sensitivity of the different FGFR3 mutations to Dovitinib, with the IC50 ranging from 70 to 90 nM for each of the various mutations. IL-6-dependent B9 cells containing vector only (B9-MINV cells are resistant to the inhibitory activity of Dovitinib at concentrations up to 1 μM. Dovitinib inhibits cell proliferation of KMS11 (FGFR3-Y373C), OPM2 (FGFR3-K650E), and KMS18 (FGFR3-G384D) cells with IC50 of 90 nM (KMS11 and OPM2) and 550 nM, respectively. Dovitinib inhibits FGF-mediated ERK1/2 phosphorylation and induces cytotoxicity in FGFR3-expressing primary MM cells. BMSCs does confer a modest degree of resistance with 44.6% growth inhibition for cells treated with 500 nM Dovitinib and cultured on stroma compared with 71.6% growth inhibition for cells grown without BMSCs. Dovitinib inhibits proliferation of M-NFS-60, an M-CSF growth-driven mouse myeloblastic cell line with a median effective concentration (EC50) of 220 nM. [1] Treatment of SK-HEP1 cells with Dovitinib results in a dose-dependent reduction in cell number and G2/M phase arrest with reduction in the G0/G1 and S phases, inhibition of anchorage-independent growth and blockage of bFGF-induced cell motility. The IC50 for Dovitinib in SK-HEP1 cells is approximately 1.7 μM. Dovitinib also significantly reduces the basal phosphorylation levels of FGFR-1, FGFR substrate 2α (FRS2-α) and ERK1/2 but not Akt in both SK-HEP1 and 21-0208 cells. In 21-0208 HCC cells, Dovitinib significantly inhibits bFGF-induced phosphorylation of FGFR-1, FRS2-α, ERK1/2 but not Akt. [2]
In vivo Dovitinib induces both cytostatic and cytotoxic responses in vivo resulting in regression of FGFR3-expressing tumors.[1] Dovitinib shows a dose- and exposure-dependent inhibition of target receptor tyrosine kinases (RTKs) expressed in tumor xenografts. Dovitinib potently inhibits tumor growth of six HCC lines. Inhibition of angiogenesis correlated with inactivation of FGFR/PDGFRβ/VEGFR2 signaling pathways. In an orthotopic model, Dovitinib potently inhibits primary tumor growth and lung metastasis and significantly prolonged mouse survival. [2] Administration of Dovitinib results in significant tumor growth inhibition and tumor regressions, including large, established tumors (500-1,000 mm3). [3]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

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.

Cell Assay: [1]

Cell lines B9 cells, MM cell lines
Concentrations 100 nM
Incubation Time 48-96 hours
Method 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.

Animal Study: [1]

Animal Models 8-week-old female BNX mice bearing KMS11 cells
Formulation 5 mM citrate buffer
Dosages 10, 30, or 60 mg/kg
Administration Gavage
Solubility 30% PEG400/0.5% Tween80/5% propylene glycol, , 30 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
1

References

[1] Trudel S, et al. Blood. 2005, 105(7), 2941-2948.

[2] Huynh H, et al. J Hepatol. 2012, 56(3), 595-601.

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Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02048943 Not yet recruiting Duct Cell Adenocarcinoma of the Pancreas|Recurrent Pancreatic Cancer|Stage III Pancreatic Cancer|Stage IV Pancreatic Cancer|Unspecified Adult Solid Tumor, Protocol Specific Roswell Park Cancer Institute|National Cancer Institute (NCI)|Novartis 2014-04 Phase 1
NCT02108782 Not yet recruiting Gastrinoma|Glucagonoma|Insulinoma|Pancreatic Polypeptide Tumor|Recurrent Islet Cell Carcinoma|Somatostatinoma Academic and Community Cancer Research United|National Cancer Institute (NCI) 2014-04 Phase 2
NCT02116803 Not yet recruiting Solid Tumors Novartis|Novartis Pharmaceuticals 2014-05 Phase 2|Phase 3
NCT02065323 Not yet recruiting Prostate Cancer Comprehensive Cancer Centers of Nevada|Oscar Goodman, Jr. 2014-05 Phase 2
NCT01994590 Not yet recruiting Prostate Cancer M.D. Anderson Cancer Center|Novartis 2014-08 Phase 2

Chemical Information

Download Dovitinib (TKI-258, CHIR-258) SDF
Molecular Weight (MW) 392.43
Formula

C21H21FN6O

CAS No. 405169-16-6
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms
Solubility (25°C) * In vitro DMSO 30 mg/mL (76 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol, 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 1-amino-5-fluoro-3-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)quinolin-2(1H)-one

Research Area

Customer Reviews (7)


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Rating
Source Oral Oncology 48 (2012) 1242–1249. Dovitinib (TKI-258, CHIR-258) purchased from Selleck
Method HNSCC xenografts
Cell Lines OSC-19 cells/SCC-1 cells/Athymic female nude mice
Concentrations 20mg/kg/day
Incubation Time 12-14 day
Results The antitumor efficacy of broad spectrum RTK inhibition was evaluated in HNSCC xenografts dosed with dovitinib (20 mg/kg/ day) orally for 12–14 days. Treatments were initiated when orthotopic tongue tumors average 10 mm2 (Fig. 2). Significant antitumor activity was seen in both OSC-19 and SCC-1 models. Growth stabilization was seen by day 2 in the SCC-1 xenografts (Fig. 2A) and by day 8 of treatment in the OSC-19 xenografts (Fig. 2B). In addition, growth reduction was seen in both SCC-1 (p < 0.0001; day 12) and OSC-19 (p < 0.0001; day 15) xenografts. During the final week of treatment, the tumors in the treatment cohort had areas of necrosis evident on gross examination which were not present in the tumors of untreated control mice.

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Rating
Source Oral Oncol, 2012, 48(12), 1242-9.. Dovitinib (TKI-258, CHIR-258) purchased from Selleck
Method Immunohistochemical and immunofluorescence analysis
Cell Lines Athymic female nude mice
Concentrations 20 mg/kg/d
Incubation Time 12-14 d
Results Treatments were initiated at time of orthotopic implantation. Growth stabilization was seen by day 8 of treatment (Fig. B). On day 17, tumors were har-vested and histological analysis was performed (Fig. C). Following Ki67 staining, tumors from control xenografts were found to have a higher percentage of proliferating cells (62%) compared to those treated with dovitinib (14%; p = 0.005). The incidence of lymph nodes metastasis was greater in the control cohort ( n = 15) com-pared to those treated with dovitinib (n = 5).

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Rating
Source Oral Oncol, 2012, 48(12), 1242-9.. Dovitinib (TKI-258, CHIR-258) purchased from Selleck
Method Cell proliferation assays
Cell Lines HNSCC /fibroblast cell lines
Concentrations 0–1000 nM
Incubation Time
Results Inhibition of RTKs by dovitinib reduced proliferation in all HNSCC and fibroblast cell lines in a dose-dependent fashion.

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Rating
Source Brit J Cancer 2010 104, 75-82. Dovitinib (TKI-258, CHIR-258) purchased from Selleck
Method Western blotting, Immunoprecipitation
Cell Lines RT112 cells
Concentrations 500 nM
Incubation Time 1 h
Results RT112 cells show constitutive activation of FGFR3 and were used to assess the effects of PD173074, SU5402 and TKI-258 on FGFR3 phosphorylation and downstream signalling (Figure B and C). A time-course of treatment with PD173074 showed a rapid and sustained inactivation of FGFR3 (Figure B). After 2 h of treatment, TKI-258 and other inhibitors all showed profound inhibition of FGFR3 phosphorylation. Recently, we have shown that FGFR3 activates the MAPK pathway in normal urothelial cells.

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Source haematologica 2011 96, 922-926. Dovitinib (TKI-258, CHIR-258) purchased from Selleck
Method Western blot, Apoptotic assay
Cell Lines Ba/F3 cells
Concentrations 0-10000 nM
Incubation Time 48 h
Results CUX1-FGFR1-expressing Ba/F3 cells displayed IL-3 independent proliferation (Figure A). Treatment of the CUX1-FGFR1-expressing Ba/F3 cells with the kinase inhibitor TKI258 significantly inhibited cell growth with an IC 50 of 489 nM (Figure B). Western blot analysis demonstrated a corresponding decrease in CUX1-FGFR1 phosphorylation with increasing doses of TKI258, while protein expression was unaffected (Figure C).Furthermore, using an Annexin-V/propidium iodide-based apoptosis assay, we could show that 48 h exposure to TKI258 induced apoptosis followed by cell death in CUX1-FGFR1-expressing Ba/F3 cells. Massive apoptosis/necrosis was recorded at 500 nM of TKI258 (Figure D).

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Rating
Source Brit J Cancer 2010 104, 75-82. Dovitinib (TKI-258, CHIR-258) purchased from Selleck
Method Cell cycle and apoptosis analysis
Cell Lines RT112/RT4/SW780/MGH-U3/97-7 cell lines
Concentrations 500 nM
Incubation Time 24 h
Results A significant increase in the proportion of cells in G1 accompanied by a decrease in S and G2 /M phases was observed in PD173074- and TKI-258-treated RT112, RT4, MGH-U3 and 97-7 cells after 24-h exposure.

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Source AACR 2011 Dovitinib (TKI-258, CHIR-258) purchased from Selleck
Method Cell viability assay
Cell Lines Ba/F3 cells
Concentrations 0-1000 nM
Incubation Time
Results

Product Citations (5)

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