405169-16-6

Compound used in treating melanoma

Dovitinib (TKI258, CHIR-258) is a multitargeted tyrosine kinase inhibitor of FLT3 and c-KIT with IC50 of 1 nM and 2 nM, respectively.

Dovitinib (TKI258, CHIR258) is a novel multi-target inhibitor for Flt3, c-Kit, FGFR1/3, VEGFR1/2/3, PDGFRα/β with IC50 of 1 nM, 2 nM, 8 nM/9 nM and 10 nM/13 nM/8 nM, 210 nM/27 nM respectively.

Dovitinib is a receptor tyrosine kinase inhibitor that targets vascular endothelial growth factor-2, basic fibroblast growth factor-1, and platelet-derived growth factor β receptors (IC50s = 65, 11, and 5 nM, respectively). By impairing these kinase signals, 1 μM dovitinib has been shown to prevent the growth and motility of pancreatic cancer cell lines (HPAF-II, BxPC-3, MiaPaCa2, and L3.6pl). At 0.04 μM, dovitinib can inhibit endothelial cell proliferation and motility. These antiangiogenic effects have been proposed to be the mechanism by which dovitinib inhibits hepatocellular carcinoma growth and metastasis. Dovitinib has been evaluated in clinical trials for the treatment of advanced solid tumors.

Dovitinib (405169-16-6) is a potent kinase inhibitor. Inhibits FLT3 (IC50 = 1 nM), c-KIT (IC50 = 2 nM), FGFR (IC50 = 8 nM), VEGFR1/2/3 (IC50 = 10 nM), PDGFRβ (IC50 = 27 nM), and CSF-1R (IC50 = 36 nM).1 Active in cell culture and in whole animals. Dovitinib selectively blocks the growth B9 cells transformed by wild type, or activated mutant FGFR3. Induces apoptosis, or sensitizes cells to induction of apoptosis by other means in a variety of cancer cell lines.

ChEBI: 4-amino-5-fluoro-3-[5-(4-methyl-1-piperazinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-quinolinone is a N-arylpiperazine.

Ethyl 2-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]acetate (compound of formula 1, 68 g) and 2-amino-6-fluorobenzonitrile (compound of formula 2, 151 g) were added to 20 times the volume of toluene, and evaporated under reduced pressure at 60°C until the volume of the solution was halved. Subsequently, nitrogen was passed through and 10 times the volume of toluene was added, the internal temperature was controlled to be below 65°C, and the toluene was removed by continued distillation under reduced pressure. To the residue, 10 times the volume of toluene was added again and nitrogen was introduced, and the moisture content was tested to be less than 300 ppm. After reaching the standard, it was cooled down to 20 ℃, and potassium tert-butanolate solid (169 g) was added directly, and the reaction was carried out at 50 ℃ for 2 h. The reaction was completed with 5 times the volume of toluene and nitrogen was added. Upon completion of the reaction, the reaction was quenched with 5 times the volume of water at room temperature to 40 °C. Subsequently, 5 times the volume of tetrahydrofuran was added to the viscous reaction solution until the solution was clarified and then washed with water to separate the organic and aqueous phases. After the organic phase was washed with saturated sodium chloride solution, the tetrahydrofuran was evaporated and heated to precipitate a solid, which was cooled and filtered to give the final product 4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one (Dovimatinib, 173 g) in 88.4% yield.

the combination of tigatuzumab and tki258 inhibited huh-7 xenograft tumor growth [3]. tki258 reduced wm tumor progression [4].

FLT3

FLT3: 1 nM (IC₅₀); c-Kit: 2 nM (IC₅₀); FGFR1: 8 nM (IC₅₀); FGFR3: 9 nM (IC₅₀); VEGFR3: 8 nM (IC₅₀); VEGFR1: 10 nM (IC₅₀); VEGFR2: 13 nM (IC₅₀); PDGFRβ: 27 nM (IC₅₀); PDGFRα: 210 nM (IC₅₀); CSF-1R: 36 nM (IC₅₀)

Store at -20°C

1) Lee et al. (2005), In vivo target modulation and biological activity of CHIR-258, a multitargeted growth factor receptor kinase inhibitor, in colon cancer models; Clin. Cancer Res., 11 3633 2) Xin et al. (2006), CHIR-258 is efficacious in a newly developed fibroblast growth factor receptor 3-expressing orthotopic multiple myeloma model in mice; Clin. Cancer Res., 12 4908