A Novel, Selective Inhibitor of Fibroblast Growth Factor Receptors That Shows a Potent Broad Spectrum of Antitumor Activity in Several Tumor Xenograft Models

Inhibition of FGF/FGFR- and VEGF/VEGFR2-mediated signaling activities in cells by LY2874455. RT-112 cells, HUVECs, KATO-III cells, and SNU-16 cells were grown and treated with LY2874455 at various concentrations (Materials and Methods). After the treatment, cells were processed and analyzed for p-Erk, p-FGFR2, and p-FRS2 levels (Materials and Methods). Adipose-derived stem cells and human erythroid colony-forming cells were grown, induced with FGF2 or VEGF, and treated with LY2874455 at various concentrations (Materials and Methods). After the treatment, tubes formed were visualized and quantified. A, inhibition of FGF2- and FGF9-induced Erk phosphorylation in HUVECs and RT-112 cells. B, inhibition of FGFR2 phosphorylation in SNU-16 and KATO-III cells. DMSO, dimethyl sulfoxide. C, inhibition of p-FRS2 in SNU-16 and KATO-III cells. D, inhibition of FGF2 (▾)- or VEGF (▪)- induced tube formation.

Inhibition of FGF- and VEGF-induced Erk and VEGFR2 phosphorylation, respectively, in mouse heart tissues by LY2874455. Mice were first treated with LY2874455 at various doses followed by tail vein injection of mouse FGF2 or VEGF (Materials and Methods). After the FGF2 or VEGF treatment, the heart tissues were collected and processed for the analysis of p-Erk and p-VEGFR2 levels by MSD ELISA assays (Materials and Methods). The plasma was also collected for the analysis of the exposures or concentrations of LY2874455 versus p-Erk or p-VEGFR2 levels (Materials and Methods). A, dose-dependent inhibition of p-Erk formation. B, exposure-dependent inhibition of p-Erk formation. C, overlay of exposures versus inhibition of p-Erk and p-VEGFR2 formation.

Effects of LY2874455 on blood pressure in rats. Animals were treated and effects on blood pressure were assessed as described in Materials and Methods. Mean arterial blood pressure was measured in rats dosed with 1 mg/kg (A), 3 mg/kg (B), and 10 mg/kg (C) of LY2874455.

Efficacy of LY2874455 in different tumor xenograft models. Mice were subcutaneously implanted with SNU-16, OPM-2, NCI-H460, and RT-112 cells (Materials and Methods). Once tumors grew to about 150 mm³, animals were randomly assigned (6–8 per group) and orally dosed with vehicle alone or LY2874455 at the indicated doses on an once or twice a day dosing schedule for 14 to 21 days (Materials and Methods). The growth of tumors was monitored and measured twice a week. A, SNU-16 tumor xenografts treated with LY2874455 (1.5 and 3 mg/kg once or twice a day). B, OPM-2 tumor xenografts treated with LY2874455 (1.5 and 3 mg/kg twice a day). C, NCI-H460 tumor xenografts treated with LY2874455 (1 and 3 mg/kg once or twice a day). D, RT-112 tumor xenografts treated with LY2874455 (3 mg/kg once or twice a day). QD, once a day; BID, twice a day.