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Purity: ≥98%
Dovitinib Lactate (formerly TKI-258 lactate; CHIR-258 lactate), a benzimidazole-quinolinone analog, is a potent, orally bioavailable and multitargeted RTK inhibitor with potential antineoplastic activity. It has an IC50 of 1 nM/2 nM and primarily inhibits class III (FLT3/c-Kit). It also has a potent IC50 of 8–13 nM against class IV (FGFR1/3) and class V (VEGFR1-4) RTKs, and a lower potency against InsR, EGFR, c-Met, EphA2, Tie2, IGFR1, and HER2. Dovitinib binds FGFR3 firmly and prevents it from being phosphorylated, which may stop tumor cell growth and cause tumor cell death.
| Targets |
FLT3 (IC50 = 1 nM); c-Kit (IC50 = 2 nM); FGFR1 (IC50 = 8 nM); FGFR3 (IC50 = 9 nM); VEGFR1 (IC50 = 1 nM); VEGFR3 (IC50 = 8 nM); VEGFR2 (IC50 = 13 nM); PDGFRα (IC50 = 27 nM); PDGFRβ (IC50 = 210 nM)
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| ln Vitro |
Dovitinib has an IC50 of 25 nM and vigorously suppresses the growth of FGF-stimulated WT and F384L-FGFR3-expressing B9 cells. Furthermore, dovitinib stops B9 cells that express each of the different FGFR3 activation mutants from proliferating. Interestingly, with the IC50 ranging from 70 to 90 nM for each of the different mutations, there are very few differences observed in the sensitivity of the different FGFR3 mutations to dovitinib. Dovitinib's inhibitory effect can be resisted by IL-6-dependent B9 cells that solely contain vector (B9-MINV cells) at concentrations as high as 1 μM. With IC50 values of 90 nM (for KMS11 and OPM2) and 550 nM (for KMS18), respectively, dovitinib suppresses the growth of KMS11 (FGFR3-Y373C), OPM2 (FGFR3-K650E), and KMS18 (FGFR3-G384D) cells. In primary MM cells expressing FGFR3, dovitinib causes cytotoxicity and inhibits FGF-mediated ERK1/2 phosphorylation. 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, BMSCs do confer a modest degree of resistance. With a median effective concentration (EC50) of 220 nM, dovitinib prevents the proliferation of M-NFS-60, an M-CSF growth-driven mouse myeloblastic cell line. Dovitinib treatment of SK-HEP1 cells causes a dose-dependent decrease in the number of cells, a G2/M phase arrest with a decrease in the G0/G1 and S phases, an inhibition of growth that is not dependent on anchorage, and a blockage of cell motility induced by bFGF. Dovitinib has an IC50 of roughly 1.7 μM in SK-HEP1 cells. In both SK-HEP1 and 21-0208 cells, dovitinib also significantly lowers the basal phosphorylation levels of FGFR-1, FGFR substrate 2α (FRS2-α), and ERK1/2, but not Akt. Dovitinib significantly inhibits bFGF-induced phosphorylation of FGFR-1, FRS2-α, and ERK1/2 in 21-0208 HCC cells, but not Akt.
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| ln Vivo |
Dovitinib causes tumors that express FGFR3 to shrink in vivo by inducing both cytotoxic and cytostatic reactions. When Target Receptor Tyrosine Kinases (RTKs) are expressed in tumor xenografts, dovitinib inhibits them in a dose- and exposure-dependent manner. The tumor growth of six HCC lines is potently inhibited by dovitinib. FGFR/PDGFRβ/VEGFR2 signaling pathway inactivation was correlated with inhibition of angiogenesis. In an orthotopic model, dovitinib markedly increased mouse survival while potently inhibiting lung metastasis and primary tumor growth. Dovitinib treatment causes large, established tumors (500–1,000 mm3) as well as notable tumor regressions and growth inhibition.
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| Enzyme Assay |
In a time-resolved fluorescence (TRF) or radioactive format, the inhibitory concentration of 50% (IC50) values for the inhibition of RTKs by dovitinib are calculated, measuring the inhibition of phosphate transfer to a substrate by the corresponding enzyme caused by dovitinib. The assay conditions for the kinase domains of FGFR3, FGFR1, PDGFRβ, and VEGFR1-3 are 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 of bovine serum albumin (BSA), 0.25 μM biotinylated peptide substrate (GGGGQDGKDYIVLPI), and 1 to 30 μM adenosine triphosphate (ATP), contingent on the Km corresponding to each enzyme. The concentration of ATP is at or slightly below Km. The pH is increased to 7.5 for the c-KIT and FLT3 reactions, and 0.2 to 8 μM ATP is added along with 0.25 to 1 μM biotinylated peptide substrate (GGLFDDPSYVNVQNL). The phosphorylated peptide is captured on streptavidin-coated microtiter plates containing stop reaction buffer (25 mM EDTA [ethylenediaminetetraacetic acid], 50 mM HEPES, pH 7.5) after reactions are incubated at room temperature for one to four hours. The DELFIA TRF system measures phosphorylated peptide using an antiphosphotyrosine antibody (PT66) labeled with europium. Using XL-Fit data analysis software version 4.1 (IDBS), nonlinear regression is used to calculate the concentration of dovitinib for IC50. At ATP concentrations near the ATP Km, the kinase activity of insulin receptor (InsR), PDGFRα, colony-stimulating factor-1 receptor (CSF-1R), and insulin-like growth factor receptor 1 (IGFR1) is inhibited.
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| Cell Assay |
The 3-(4,5-dimethylthiazol)-2,5-diphenyl tetrazolium (MTT) dye absorbance represents the cell viability. Densities of 5 × 103 (B9 cells) or 2 × 104 (MM cell lines) cells per well are used for seeding cells in 96-well plates. To culture the cells, different concentrations of Dovitinib are added along with 30 ng/mL aFGF, 100 μg/mL heparin, or 1% IL-6 as needed. Aliquots of 10 μL of drug or DMSO diluted in culture medium are added for each concentration of dovitinib. Drug combination studies involve incubating cells with either 100 nM Dovitinib or 0.5 μM dexamethasone, or both at the same time if necessary. In order to assess the impact of Dovitinib on the growth of MM cells adherent to BMSCs, 104 KMS11 cells are cultured in the presence or absence of Dovitinib on 96-well plates coated with BMSCs. The incubation period for plates is 48–96 hours. 5 × 103 M-NFS-60 cells/well are cultured with serial dilutions of Dovitinib with 10 ng/mL M-CSF and without granulocyte-macrophage colony-stimulating factor (GM-CSF) in order to evaluate the growth of M-CSF-mediated macrophage colony-growth. Using the Cell Titer-Glo Assay, cell viability is assessed after 72 hours. Every experimental condition is run through three times.
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| References |
| Molecular Formula |
C24H27FN6O4
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| Molecular Weight |
482.51
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| Exact Mass |
500.21834621
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| Elemental Analysis |
C, 59.74; H, 5.64; F, 3.94; N, 17.42; O, 13.26
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| CAS # |
915769-50-5
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| Related CAS # |
Dovitinib lactate;692737-80-7;Dovitinib;405169-16-6;Dovitinib dilactic acid;852433-84-2
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| Appearance |
white solid powder
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| SMILES |
CC(C(=O)O)O.CN1CCN(CC1)C2=CC3=C(C=C2)N=C(N3)C4=C(C5=C(C=CC=C5F)NC4=O)N.O
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| InChi Key |
QDPVYZNVVQQULH-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H21FN6O.C3H6O3.H2O/c1-27-7-9-28(10-8-27)12-5-6-14-16(11-12)25-20(24-14)18-19(23)17-13(22)3-2-4-15(17)26-21(18)29;1-2(4)3(5)6;/h2-6,11H,7-10H2,1H3,(H,24,25)(H3,23,26,29);2,4H,1H3,(H,5,6);1H2
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| Chemical Name |
4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one;2-hydroxypropanoic acid;hydrate
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0725 mL | 10.3625 mL | 20.7250 mL | |
| 5 mM | 0.4145 mL | 2.0725 mL | 4.1450 mL | |
| 10 mM | 0.2072 mL | 1.0362 mL | 2.0725 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01576380 | Completed | Drug: TKI258 | Linitis Plastica Neoplasms |
Novartis Pharmaceuticals | June 2012 | Phase 2 |
| NCT01155713 | Completed | Drug: TKI258 | Neoplasm Cancer |
Novartis Pharmaceuticals | July 2010 | Phase 1 |
| NCT01030055 | Completed | Drug: TKI258 (dovitinib) |
Neoplasm Cancer |
Novartis Pharmaceuticals | February 2010 | Phase 1 |
| NCT01155713 | Completed | Drug: TKI258 | Advanced Solid Tumors | Novartis Pharmaceuticals | September 2008 | Phase 1 |
| NCT02116803 | Completed | Drug: dovitinib Drug: fulvestrant |
Solid Tumors | Novartis Pharmaceuticals | May 28, 2014 | Phase 2 Phase 3 |
CHIR-258 inhibits the viability of FGFR3-expressing B9 cells but not parental IL-6-stimulated cells. Blood. 2005 Apr 1;105(7):2941-8. |
CHIR-258 inhibits viability of KMS11 cells in the presence of IL-6, IGF-1, and BMSCs. Blood. 2005 Apr 1;105(7):2941-8. |
CHIR-258 inhibits FGFR3 phosphorylation and demonstrates antitumor effects in vivo. Blood. 2005 Apr 1;105(7):2941-8. |
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