Cas：405169-16-6 (free base)
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.
Chemical Formula: C21H21FN6O
Exact Mass: 392.1761
Molecular Weight: 392.4384
Elemental Analysis: C, 64.27; H, 5.39; F, 4.84; N, 21.42; O, 4.08
InChi Code: InChI=1S/C21H21FN6O/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/h2-6,11H,7-10H2,1H3,(H,24,25)(H3,23,26,29)
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO
Shelf Life: >3 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.03.00
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.
Shivapurkar N, Vietsch EE, Carney E, Isaacs C, Wellstein A. Circulating microRNAs in patients with hormone receptor-positive, metastatic breast cancer treated with dovitinib. Clin Transl Med. 2017 Oct 4;6(1):37. doi: 10.1186/s40169-017-0169-y. PubMed PMID: 28980224; PubMed Central PMCID: PMC5628092.
Landberg N, Dreimane A, Rissler M, Billstrom R, Ågerstam H. Primary cells in BCR/FGFR1-positive 8p11 myeloproliferative syndrome are sensitive to dovitinib, ponatinib, and dasatinib. Eur J Haematol. 2017 Nov;99(5):442-448. doi: 10.1111/ejh.12957. Epub 2017 Oct 4. PubMed PMID: 28881484.
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