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

  • J Med Chem. 2016 May 26;59(10):4651-63. doi: 10.1021/acs.jmedchem.5b02021.
Riccardo Castelli  1 ,  Arianna Giacomini  2 ,  Mattia Anselmi  1 ,  Nicole Bozza  1 ,  Federica Vacondio  1 ,  Silvia Rivara  1 ,  Sara Matarazzo  2 ,  Marco Presta  2 ,  Marco Mor  1 ,  Roberto Ronca  2
Affiliations
  • 1. Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, I-43124, Parma, Italy.
  • 2. Dipartimento di Medicina Molecolare e Traslazionale, Università degli Studi di Brescia , Via Branze 39, I-25123, Brescia, Italy.
PMID: 27138345 DOI: 10.1021/acs.jmedchem.5b02021
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.

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