Dovitinib lactate (CHIR-258 lactate)

Dovitinib(CHIR-258; TKI258) lactate is a potent inhibitor of fibroblast growth factor receptor 3 (FGFR3) with an IC50 of 5 nM.

Dovitinib potently inhibits FGFR3 with an IC50 of 5 nM in in vitro kinase assays and selectively inhibits the growth of B9 cells and human myeloma cell lines expressing wild-type or activated mutant FGFR3. Addition of interleukin 6 (IL-6) or insulin growth factor 1 or coculture on stroma does not confer resistance to dovitinib. In primary myeloma cells dovitinib inhibits downstream extracellular signal-regulated kinase (ERK) 1/2 phosphorylation with an associated cytotoxic response[1]. Treatment of SK-HEP1 cells with dovitinib results in G2/M cell cycle arrest, inhibition of colony formation in soft agar and blockade of bFGF-induced cell migration. Dovitinib inhibits basal expression and FGF-induced phosphorylation of FGFR-1, FRS2-α and ERK1/2[2].

Dovitinib demonstrates significant antitumor and antimetastatic activities in HCC xenograft models. Dovitinib potently inhibits tumor growth of six HCC lines. Inhibition of angiogenesis correlates with inactivation of FGFR/PDGFR-β/VEGFR-2 signaling pathways. Dovitinib also causes dephosphorylation of retinoblastoma, upregulation of p-histone H2A-X and p27, and downregulation of p-cdk-2 and cyclin B1, which results in a reduction in cellular proliferation and the induction of tumor cell apoptosis[2].

[1]. Trudel S, et al. CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood. 2005, 105(7), 2941-2948. [2]. Huynh H, et al. Dovitinib demonstrates antitumor and antimetastatic activities in xenograft models of hepatocellular carcinoma. J Hepatol. 2012, 56(3), 595-601.