Dovitinib (TKI258) Lactate
Catalog No.S7765 Synonyms: CHIR258
Molecular Weight(MW): 482.51
Dovitinib (TKI258) Lactate is the Lactate of Dovitinib, which 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, IGFR1 and HER2. Phase 4.
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(c) Percent survival for the AGS cancer cell line is shown with FGFR2 inhibitors of varying specificity. (d) The KatoIII diffuse gastric cancer cell line was treated with FGFR2 inhibitors of varying specificity. The Y-axis depicts percent survival versus the X-axis with log concentrations. In all panels, error bars represent standard error of the mean. The difference in percent cell survival between KatoIII and AGS cells was statistically significant (P <0.05) at the three highest concentrations of all drugs, except Brivanib which was only significant at the highest concentration.
Genome Biol, 2014, 15(8):428.. Dovitinib (TKI258) Lactate purchased from Selleck.
Stable BaF3.FGFR2 cells were pretreated in IL-3-free BaF3 media for 90 minutes at 37°C. After the 90-minute incubation period, the media were removed and the cells were incubated for 7.5 minutes at 37°C with media containing 5 µg/ml heparan sulfate and 16 nM FGF10. Cells were lysed in lysis buffer containing phosphatase inhibitors and 150 µg of total protein was separated on an SDS-PAGE, transferred to a nitrocellulose membrane, and probed using an anti-pan-phospho-FGFR, anti-FGFR2 (BEK-C17), and anti-tubulin antibodies.
Neoplasia, 2013, 15(8):975-88. Dovitinib (TKI258) Lactate purchased from Selleck.
The small molecule kinase inhibitor dovitinib can partially reverse the effects of FGF-2. Quantification of centrosome aberrations (A), mitotic defects (B), deviations from the modal number of chromosome 8 (C) and Comet assay features of DNA damage (D–F). LNCaP cells were treated with dH2O (control for rFGF-2), 10 ng/ml rFGF-2, 0.1% DMSO (control for dovitinib), 1μM dovitinib or both rFGF-2 and dovitinib for 72 hour. Note that dovitinib could partially reverse the effects of rFGF-2 on the observed cellular alterations. Mean and standard error of at least 3 independent experiments are shown. Asterisks indicate the statistical significance level as indicated above with cells treated with FGF-2 alone used as reference.
Urol Oncol, 2018, 36(8):365. Dovitinib (TKI258) Lactate purchased from Selleck.
IM-9 cells were treated with 0, 1, or 3 μM dovitinib for 24 h. After protein concentration determination, the expression levels in the cytosolic (C) and nuclear (N) fractions were measured by western blot analysis. Actin and histone H3 were used as loading controls.
Amino Acids, 2016, 48(7):1591-9. Dovitinib (TKI258) Lactate purchased from Selleck.
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|Description||Dovitinib (TKI258) Lactate is the Lactate of Dovitinib, which 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, IGFR1 and HER2. Phase 4.|
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.  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. 
|In vivo||Dovitinib induces both cytostatic and cytotoxic responses in vivo resulting in regression of FGFR3-expressing tumors. 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.  Administration of Dovitinib results in significant tumor growth inhibition and tumor regressions, including large, established tumors (500-1,000 mm3). |
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||DMSO||100 mg/mL (207.24 mM)|
|Water||66 mg/mL warmed (136.78 mM)|
|Ethanol||1 mg/mL warmed (2.07 mM)|
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Clinical Trial Information
|NCT Number||Recruitment||interventions||Conditions||Sponsor/Collaborators||Start Date||Phases|
|NCT02268435||Withdrawn||Drug: dovitinib plus imatinib||Gastrointestinal Stromal Tumors||Asan Medical Center||March 2015||Phase 1|
|NCT01700270||Completed||Drug: dovitinib (TKI258)|Drug: fluvoxamine||Advanced Solid Tumors Excluding Breast Cancer||Novartis Pharmaceuticals|Novartis||May 2013||Phase 1|
|NCT01680796||Withdrawn||Drug: Dovitinib|Drug: Bortezomib|Drug: Dexamethasone||Multiple Myeloma||University of Florida|Novartis Pharmaceuticals||February 2013||Phase 1|
|NCT01266070||Terminated||Drug: Dovitinib||Von Hippel-Lindau Syndrome||M.D. Anderson Cancer Center|Novartis||November 2012||Phase 2|
|NCT01515969||Terminated||Drug: Erlotinib hydrochloride|Drug: Dovitinib lactate||Non-small Cell Lung Cancer (NSCLC) Recurrent|Non-small Cell Lung Cancer (NSCLC) Stage IV||Heather Wakelee|Genentech Inc.|Novartis|Stanford University||July 2012||Phase 1|
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