Dovitinib (TKI258) potently inhibited FLT3, c-KIT, FGFR, VEGFR1/2/3, PDGFRß and CSF-1R with IC50 values of 1, 2, 5, 10, 8, 27, 36 nM respectively. Dovitinib selectively blocked the growth of wild-type (WT) or activated mutant FGFR3-transformed B9 cells and human myeloma cell lines. Dovitinib was an effective treatment in a xenograft mouse model of FGFR3 multiple myeloma.
|Cell lines||J807C, Y373C, K650E, G384D, wild type (WT), F384L and B9-MINV cells|
|Preparation method||Viability assay.
Cell viability was assessed by 3-(4,5-dimethylthiazol)-2,5-diphenyl tetrazolium (MTT) dye absorbance according to the manufacturer's instructions (Boehringer Mannheim, Mannheim, Germany). Cells were seeded in 96-well plates at a density of 5000 (B9 cells) or 20 000 (MM cell lines) cells per well. Cells were incubated with 30 ng/mL aFGF and 100 μg/mL heparin or 1% IL-6 where indicated and increasing concentrations of CHIR-258. For each concentration of CHIR-258, 10-μL aliquots of drug or DMSO diluted in culture medium was added. For drug combination studies, cells were incubated with 0.5 μM dexamethasone, 100 nM CHIR-258, or both simultaneously where indicated. To evaluate the effect of CHIR-258 on growth of MM cells adherent to BMSCs, 10 000 KMS11 cells were cultured on BMSC-coated 96-well plates in the presence or absence of CHIR-258. Plates were incubated for 48 to 96 hours.
|Concentrations||0~400 n M|
|Incubation time||48 h|
|Animal models||KMS11 cells xenograft mouse model|
|Formulation||5 mM citrate buffer|
|Dosages||10, 30, or 60 mg/kg daily for 21 days|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma.
Sivanand et al. Sci Transl Med. 2012 Jun 6;4(137):137ra75. PMID: 22674553.
Population Pharmacokinetic/Pharmacodynamic Modeling to Assist Dosing Schedule Selection for Dovitinib.
Wang et al. J Clin Pharmacol. 2012 Jan 27. PMID: 22287694.
Dovitinib sensitizes hepatocellular carcinoma cells to TRAIL and tigatuzumab, a novel anti-DR5 antibody, through SHP-1-dependent inhibition of STAT3.
Chen et al. Biochem Pharmacol. 2012 Mar 15;83(6):769-77. PMID: 22230479.
Dovitinib induces apoptosis and overcomes sorafenib resistance in hepatocellular carcinoma through SHP-1-mediated inhibition of STAT3.
Tai et al. Mol Cancer Ther. 2012 Feb;11(2):452-63. PMID: 22180308.
Dovitinib demonstrates antitumor and antimetastatic activities in xenograft models of hepatocellular carcinoma.
Huynh et al. J Hepatol. 2012 Mar;56(3):595-601. PMID: 22027573.
Phase I/II and pharmacodynamic study of dovitinib (TKI258), an inhibitor of fibroblast growth factor receptors and VEGF receptors, in patients with advanced melanoma.
Kim et al. Clin Cancer Res. 2011 Dec 1;17(23):7451-61. PMID: 21976540.
CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma.
Trudel S, et al. Blood. 2005 Apr 1;105(7):2941-8. PMID: 15598814.
|Related VEGFR/PDGFR Products|
Avapritinib (BLU-285) is a small molecule kinase inhibitor that potently inhibits PDGFRα D842V mutant activity in vitro (IC50 = 0.5 nM) and PDGFRα D842V autophosphorylation in the cellular setting (IC50 = 30 nM); also a potent inhibitor of the analogous KIT mutation, D816V in KIT Exon 17 (IC50 = 0.5 nM).
|Nintedanib Ethanesulfonate Salt
BIBF 1120 esylate is a potent triple angiokinase inhibitor for VEGFR1/2/3, FGFR1/2/3 and PDGFRα/β with IC50s of 34 nM/13 nM/13 nM, 69 nM/37 nM/108 nM and 59 nM/65 nM, respectively.
Regorafenib (BAY 73-4506) is a multi-target inhibitor for VEGFR1, VEGFR2, VEGFR3, PDGFRβ, Kit, RET and Raf-1 with IC50 of 13 nM/4.2 nM/46 nM, 22 nM, 7 nM, 1.5 nM and 2.5 nM, respectively.
|Pazopanib HCl (GW786034 )
Pazopanib HCl (GW786034 HCl) is a novel multi-target inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFR, FGFR, c-Kit and c-Fms with IC50 of 10 nM, 30 nM, 47 nM, 84 nM, 74 nM, 140 nM and 146 nM in cell-free assays, respectively.
|Dovitinib (TKI-258) Dilactic Acid
Dovitinib Dilactic acid (TKI258 Dilactic acid) is the Dilactic acid of Dovitinib, which is a multitargeted RTK inhibitor, mostly for class III (FLT3/c-Kit) with IC50 of 1 nM/2 nM.
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