Synthesis, Structural Elucidation, and Biological Evaluation of NSC12, an Orally Available Fibroblast Growth Factor (FGF) Ligand Trap for the Treatment of FGF-Dependent Lung Tumors

Abstract

NSC12 is an orally available pan-FGF trap able to inhibit FGF2/FGFR interaction and endowed with promising antitumor activity. It was identified by virtual screening from a NCI small molecule library, but no data were available about its synthesis, stereochemistry, and physicochemical properties. We report here a synthetic route that allowed us to characterize and unambiguously identify the structure of the active compound by a combination of NMR spectroscopy and in silico conformational analysis. The synthetic protocol allowed us to sustain experiments aimed at assessing its therapeutic potential for the treatment of FGF-dependent lung cancers. A crucial step in the synthesis generated a couple of diastereoisomers, with only one able to act as a FGF trap molecule and to inhibit FGF-dependent receptor activation, cell proliferation, and tumor growth when tested in vitro and in vivo on murine and human lung cancer cells.

Long Pentraxin 3-Mediated Fibroblast Growth Factor Trapping Impairs Fibrosarcoma Growth

“…On this basis, to assess the effect of the local/systemic delivery of PTX3 protein on fibrosarcoma growth, wild type MC17-51 cells were injected in syngeneic wild type (C57BL/6) and transgenic TgN(Tie2-hPTX3) mice that overexpress human PTX3 under the endothelial specific Tie2 promoter ( 17 ). In line with the in vivo data herewith obtained with fibrosarcoma PTX3 transfectants (see above) and previous observations on different FGF-dependent tumor types grafted in TgN(Tie2-hPTX3) mice ( 17 , 24 ), endothelial expression and stroma accumulation of PTX3 significantly impaired the growth of fibrosarcoma MC17-51 tumor grafts in these animals. This resulted in reduced average weight of the lesions harvested from transgenic mice when compared to wild type animals (Figure 3C ).…”

“…The PTX3-derived small molecule NSC12 represents the first low molecular weight FGF-trap endowed with significant implications for the therapy of FGF-dependent tumors ( 17 , 24 ). Thus, in a translational effort to exploit the FGF-blocking activity exerted by PTX3 on fibrosarcoma cells, we evaluated the effect of this novel FGF trap on the tumorigenic potential of human HT-1080 cells in vitro and in vivo .…”

Fibroblast growth factor modulates mast cell recruitment in a murine model of prostate cancer

“…Compound NSC12 was synthesized by M. Mor (University of Parma, Italy) as described [ 47 ] and control compound NSC21 was provided by Drug Synthesis and Chemistry Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute (USA). Human recombinant FGF2 was from Tecnogen (Caserta, Italy).…”

FGF/FGFR signaling in health and disease

“…In tumor models, administration of NSC12 can block the growth, angiogenesis, and metastasis of FGF-dependent lung tumors. 732 In addition, a soluble FGFR2 mutant with S252W (sFGFR2IIIc (S252W)) was found to partially alleviate the AS in mice by alleviating the premature closure of coronal suture in cultured calvarias and transgenic mice. 733,734 Moreover, sFGFR3, a recombinant protein, acts as a FGFR trap to prevent FGF ligand binding to FGFR3.…”