Dovitinib, also known as TKI-258 or CHIR-258, is an orally bioavailable FGFR3 inhibitor, which strongly binds to fibroblast growth factor receptor 3 (FGFR3) and inhibits its phosphorylation, which may result in the inhibition of tumor cell proliferation and the induction of tumor cell death. In addition, this agent may inhibit other members of the RTK superfamily, including the vascular endothelial growth factor receptor; fibroblast growth factor receptor 1; platelet-derived growth factor receptor type 3; FMS-like tyrosine kinase 3; stem cell factor receptor (c-KIT); and colony-stimulating factor receptor 1; this may result in an additional reduction in cellular proliferation and angiogenesis, and the induction of tumor cell apoptosis.
CAS Number: 405169-16-6
Molecular Weight: 392.43
Chemical Name: 4-Amino-5-fluoro-3-[6-(4-methyl-1-piperazinyl)-1H-benzimidazol-2-yl]-2(1H)-quinolinon
Appearance: Solid Power.
Purity: ≥98% (or refer to the Certificate of Analysis)
Solubility: Soluble in DMSO
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis
Storage Condition: Dry, dark and -20 oC for 1 year or refer to the Certificate of Analysis.
Shelf Life: ≥12 months if stored properly.
Stock Solution Storage: 0 - 4 oC for 1 month or refer to the Certificate of Analysis.
Drug Formulation: To be determined.
HS Tariff Code: 382200
How to use
Dovitinib potently inhibits the FGF-stimulated growth of WT and F384L-FGFR3-expressing B9 cells with IC50 values of 25 nM. 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 values of 90 nM (KMS11 and OPM2) and 550 nM, respectively. Dovitinib 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. Dovitinib enhances the BMP-2-induced alkaline phosphatase (ALP) induction, which is a representative marker of osteoblast differentiation. Dovitinib also stimulates the translocation of phosphorylated Smad1/5/8 into the nucleus and phosphorylation of mitogen-activated protein kinases, including ERK1/2 and p38. Dovitinib strongly inhibits both the interaction of TNIK with ATP (Ki, 13 nM) and the activation of Wnt signaling effectors such as β-catenin and TCF4. Dovitinib also induces caspase-dependent apoptosis in IM-9 cells without significant cytotoxicity in PBMCs.
Dovitinib (10 mg/kg, 30 mg/kg, 60 mg/kg, p.o.) shows significant antitumor effect in the KMS11-bearing mice model, and the growth inhibition is 48%, 78.5%, and 94% in the 10 mg/kg, 30 mg/kg, and 60 mg/kg treatment arms, respectively, compared with the placebo-treated mice. Dovitinib (50 and 75 mg/kg) results in 97% and 98% tumor growth inhibition, respectively, and the maximal efficacy is at 50 mg/kg.
- PilieP, Hasanov E, Matin SF, Woodson AHH, Marcott VD, Bird S, Slack RS, Fuller GN, McCutcheon IE, Jonasch E. Pilot study of dovitinib in patients with von Hippel-Lindau disease. Oncotarget. 2018 May 4;9(34):23390-23395. doi: 10.18632/oncotarget.25171. eCollection 2018 May 4. PubMed PMID: 29805741; PubMed Central PMCID: PMC5955100.
- Choi YJ, Kim HS, Park SH, Kim BS, Kim KH, Lee HJ, Song HS, Shin DY, Lee HY, Kim HG, Lee KH, Lee JL, Park KH. Phase II Study of Dovitinib in Patients with Castration-Resistant Prostate Cancer (KCSG-GU11-05). Cancer Res Treat. 2018 Jan 2. doi: 10.4143/crt.2017.438. [Epub ahead of print] PubMed PMID: 29334610.
- de Weger VA, Goel S, von Moos R, Schellens JHM, Mach N, Tan E, Anand S, Scott JW, Lassen U. A drug-drug interaction study to assess the effect of the CYP1A2 inhibitor fluvoxamine on the pharmacokinetics of dovitinib (TKI258) in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2018 Jan;81(1):73-80. doi: 10.1007/s00280-017-3469-4. Epub 2017 Nov 3. PubMed PMID: 29101463.
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