title: Integrating computational and chemical biology tools in the discovery of antiangiogenic small molecule ligands of FGF2 derived from endogenous inhibitors.
abstract: The FGFs/FGFRs system is a recognized actionable target for therapeutic approaches aimed at inhibiting tumor growth, angiogenesis, metastasis, and resistance to therapy. We previously identified a non-peptidic compound (SM27) that retains the structural and functional properties of the FGF2-binding sequence of thrombospondin-1 (TSP-1), a major endogenous inhibitor of angiogenesis. Here we identified new small molecule inhibitors of FGF2 based on the initial lead. A similarity-based screening of small molecule libraries, followed by docking calculations and experimental studies, allowed selecting 7 bi-naphthalenic compounds that bound FGF2 inhibiting its binding to both heparan sulfate proteoglycans and FGFR-1. The compounds inhibit FGF2 activity in in vitro and ex vivo models of angiogenesis, with improved potency over SM27. Comparative analysis of the selected hits, complemented by NMR and biochemical analysis of 4 newly synthesized functionalized phenylamino-substituted naphthalenes, allowed identifying the minimal stereochemical requirements to improve the design of naphthalene sulfonates as FGF2 inhibitors.
authors.affiliation: Tumor Angiogenesis Unit, Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, 24126 Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Foglieni
authors.affiliation: Laboratorio NMR, Istituto per lo Studio delle Macromolecole, Consiglio Nazionale delle Ricerche, Milano, 20133 Italy.
authors.forename: Katiuscia
authors.initials: K
authors.lastname: Pagano
authors.affiliation: Dipartimento di Chimica e Chimica Industriale, Università Di Pisa, Pisa, 56124, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Lessi
authors.affiliation: Section of Experimental Oncology and Immunology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, 25123 Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Bugatti
authors.affiliation: Istituto di Chimica del Riconoscimento Molecolare, Consiglio Nazionale delle Ricerche, Milano, 20131 Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Moroni
authors.affiliation: Tumor Angiogenesis Unit, Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, 24126 Italy.
authors.forename: Denise
authors.initials: D
authors.lastname: Pinessi
authors.affiliation: Tumor Angiogenesis Unit, Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, 24126 Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Resovi
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, 70121 Italy, and National Cancer Institute "Giovanni Paolo II", Bari, 70124 Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Ribatti
authors.affiliation: Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni, Milano 20133, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Bertini
authors.affiliation: Laboratorio NMR, Istituto per lo Studio delle Macromolecole, Consiglio Nazionale delle Ricerche, Milano, 20133 Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Ragona
authors.affiliation: Dipartimento di Chimica e Chimica Industriale, Università Di Pisa, Pisa, 56124, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Bellina
authors.affiliation: Section of Experimental Oncology and Immunology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, 25123 Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Rusnati
authors.affiliation: Istituto di Chimica del Riconoscimento Molecolare, Consiglio Nazionale delle Ricerche, Milano, 20131 Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Colombo
authors.affiliation: Tumor Angiogenesis Unit, Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, 24126 Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Taraboletti
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D019295:Computational Biology; D055808:Drug Discovery; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy
chemical_list: D020533:Angiogenesis Inhibitors; D008024:Ligands; D016222:Fibroblast Growth Factor 2