title: 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.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, I-43124, Parma, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Castelli
authors.affiliation: Dipartimento di Medicina Molecolare e Traslazionale, Università degli Studi di Brescia , Via Branze 39, I-25123, Brescia, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Giacomini
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, I-43124, Parma, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Anselmi
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, I-43124, Parma, Italy.
authors.forename: Nicole
authors.initials: N
authors.lastname: Bozza
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, I-43124, Parma, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Vacondio
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, I-43124, Parma, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.affiliation: Dipartimento di Medicina Molecolare e Traslazionale, Università degli Studi di Brescia , Via Branze 39, I-25123, Brescia, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Matarazzo
authors.affiliation: Dipartimento di Medicina Molecolare e Traslazionale, Università degli Studi di Brescia , Via Branze 39, I-25123, Brescia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Presta
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, I-43124, Parma, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.affiliation: Dipartimento di Medicina Molecolare e Traslazionale, Università degli Studi di Brescia , Via Branze 39, I-25123, Brescia, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Ronca
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002784:Cholesterol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C000619427:NSC172285; D005346:Fibroblast Growth Factors; D002784:Cholesterol