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D-3608 Dovitinib, Free Base, >99%

[CHIR-258] [TKI-258]

M.W. 392.43

C21H21FN6O

[405169-16-6]

Storage:  Store at or below -20 ºC.  Solubility:  Soluble in DMSO.  Disposal:  A

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• Dovitinib is a small-molecule multitargeted receptor tyrosine kinase inhibitor.

• Dovitinib inhibited Ba/F3 cells transformed to IL3 independence by ZNF198-FGFR1 or BCR-FGFR1 with IC50 values of 150 nM and 90 nM, respectively.  The phosphorylation of each fusion gene, ERK, and STAT5 was inhibited as well at the same time.  Dovitinib treatment also inhibited proliferation and survival of the FGFR1OP2-FGFR1-positive KG1 and KG1A cell lines and resulted in cell apoptosis.  Furthermore, dovitinib significantly inhibited the survival of primary cells from 8p11 myeloproliferative syndrome (EMS) patients dose-dependently.  Chase, A., et al.  "Activity of TKI258 against primary cells and cell lines with FGFR1 fusion genes associated with the 8p11 myeloproliferative syndrome."  Blood 110:  3729-3734 (2007).

• Dovitinib potently inhibits fibroblast growth factor receptor 3 (FGFR3) with an IC50 of 5 nM in in vitro kinase assays and selectively blocked the growth of B9 cells and human myeloma cell lines expressing wild-type (WT) or activated mutant FGFR3.  Dovitinib was effective against a xenograft mouse model of FGFR3 multiple myeloma (MM).  Trudel, S., et al.  "CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma."  Blood 105:  2941-2948 (2005).

• Dovitinib treatment induces tumor growth inhibition, stabilization, or regression in xenograft models of human colon cancer, including large, established tumors (500-1,000 mm3).  Dovitinib inhibited the phosphorylation of PDGFR-β and ERK in tumors within 2 hours following dosing and the inhibitory activity was sustained for more than 24 hours.  Lee, S.H., et al.  "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:  3633-3641 (2005).

• Dovitinib was examined on two human leukemic cell lines with differing FLT3 mutational status in vitro and in vivo, including MV4;11 cells expressing FLT3 internal tandem duplications (ITD) and RS4;11 cells with wild-type (WT) FLT3.  Antiproliferative activity of dovitinib against MV4;11 was about 24-fold greater when compared with RS4;11.  These results indicate that dovitinib more potently inhibits cells with constitutively activated FLT3 ITD.  Lopes de Menezes, D.E., et al.  "CHIR-258:  a potent inhibitor of FLT3 kinase in experimental tumor xenograft models of human acute myelogenous leukemia."  Clin. Cancer Res. 11:  5281-5291 (2005).

• Daily oral administration of dovitinib, at doses that inhibited FGFR3 signaling in KMS-11-luc tumors in vivo, resulted in a significant inhibition of KMS-11-luc tumor growth and a significant improvement in animal survival.  Xin, X., et al.  "CHIR-258 is efficacious in a newly developed fibroblast growth factor receptor 3-expressing orthotopic multiple myeloma model in mice."  Clin. Cancer Res. 12:  4908-4915 (2006).

• Sold for laboratory or manufacturing purposes only; not for human, veterinary, food, or household use.

• This product is offered for R&D use in accordance with (i) 35 USC 271(e)+A13(1) in the U.S.; (ii) Section 69.1 of Japanese Patent Law in Japan; (iii) Section 11, No. 2 of the German Patent Act of 1981 in Germany; (iv) Section 60, Paragraph 5b of the U.K. Patents Act of 1977 in the U.K.; (v) Sections 55.2(1) and 55.2(6) and other common law exemptions of Canadian patent law; (vi) Section 68B of the Patents Act of 1953 in New Zealand together with the amendment of same by the Statutes Amendment Bill of 2002; (vii) such related legislation and/or case law as may be or become applicable in the aforementioned countries; and (viii) such similar laws and rules as may apply in various other countries.

• Not available in some countries; not available to some institutions; not available for some uses.