Abstract
Fibroblast growth factors (FGFs) are recognized targets for the development of therapies against angiogenesis-driven diseases, including cancer. The formation of a ternary complex with the transmembrane tyrosine kinase receptors (FGFRs), and heparan sulphate proteoglycans (HSPGs) is required for FGF2 pro-angiogenic activity. Here by using a combination of techniques including Nuclear Magnetic Resonance, Molecular Dynamics, Surface Plasmon Resonance and cell-based binding assays we clarify the molecular mechanism of inhibition of an angiostatic small molecule, sm27, mimicking the endogenous inhibitor of angiogenesis, thrombospondin-1. NMR and MD data demonstrate that sm27 engages the heparin-binding site of FGF2 and induces long-range dynamics perturbations along FGF2/FGFR1 interface regions. The functional consequence of the inhibitor binding is an impaired FGF2 interaction with both its receptors, as demonstrated by SPR and cell-based binding assays. We propose that sm27 antiangiogenic activity is based on a twofold-direct and allosteric-mechanism, inhibiting FGF2 binding to both its receptors.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Allosteric Regulation / drug effects
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Angiogenesis Inhibitors / chemistry
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Angiogenesis Inhibitors / pharmacology*
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Fibroblast Growth Factor 2 / antagonists & inhibitors*
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Fibroblast Growth Factor 2 / chemistry*
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Heparan Sulfate Proteoglycans / antagonists & inhibitors*
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Heparan Sulfate Proteoglycans / chemistry*
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Humans
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In Vitro Techniques
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Models, Molecular
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Molecular Dynamics Simulation
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Molecular Mimicry
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Multiprotein Complexes / antagonists & inhibitors
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Multiprotein Complexes / chemistry
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Naphthalenesulfonates / chemistry
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Naphthalenesulfonates / pharmacology
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Nuclear Magnetic Resonance, Biomolecular
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Protein Interaction Mapping
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Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors*
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Receptor, Fibroblast Growth Factor, Type 1 / chemistry*
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Surface Plasmon Resonance
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Thrombospondin 1 / chemistry
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Thrombospondin 1 / pharmacology
Substances
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Angiogenesis Inhibitors
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Heparan Sulfate Proteoglycans
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Multiprotein Complexes
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Naphthalenesulfonates
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Thrombospondin 1
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Fibroblast Growth Factor 2
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FGFR1 protein, human
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Receptor, Fibroblast Growth Factor, Type 1