Direct and allosteric inhibition of the FGF2/HSPGs/FGFR1 ternary complex formation by an antiangiogenic, thrombospondin-1-mimic small molecule.

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.

Combined in silico and experimental approach for drug design: the binding mode of peptidic and non-peptidic inhibitors to hsp90 N-terminal domain.

Heat shock protein 90 (Hsp90) is a prime target for antitumor therapies. The information obtained by molecular dynamics (MD) simulations is combined with NMR data to provide a cross-validated atomic resolution model of the complementary interactions of heat shock protein 90 with a peptidic (shepherdin) and a non-peptidic (5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside, AICAR) inhibitor, showing antiproliferative and proapoptotic activity in multiple tumor cell lines. This approach highlights the relevant role of imidazolic moiety in the interaction of both antagonist molecules.

A quantitative method to assess muscle tissue oxygenation in vivo by monitoring 1H nuclear magnetic resonance myoglobin resonances.

A nuclear magnetic resonance (NMR) method was implemented to assess in vivo oxygenation levels by a quantitative determination of the 1H NMR myoglobin (Mb) resonances. The proximal His-F8 NdeltaH at 70-90 ppm and Val-E11 gammaCH3 resonance at -2.8 ppm, reflecting deoxygenated (deoxy-Mb) and oxygenated (met-Mb) states, were alternately recorded.

Non-peptidic thrombospondin-1 mimics as fibroblast growth factor-2 inhibitors: an integrated strategy for the development of new antiangiogenic compounds.

Endogenous inhibitors of angiogenesis, such as thrombospondin-1 (TSP-1), are promising sources of therapeutic agents to treat angiogenesis-driven diseases, including cancer. TSP-1 regulates angiogenesis through different mechanisms, including binding and sequestration of the angiogenic factor fibroblast growth factor-2 (FGF-2), through a site located in the calcium binding type III repeats. We hypothesized that the FGF-2 binding sequence of TSP-1 might serve as a template for the development of inhibitors of angiogenesis.

Fibroblast growth factor-2 antagonist and antiangiogenic activity of long-pentraxin 3-derived synthetic peptides.

Angiogenesis and inflammation are closely integrated processes. Fibroblast growth factor-2 (FGF2) is a prototypic angiogenesis inducer belonging to the family of the heparin-binding FGF growth factors. FGF2 exerts its pro-angiogenic activity by interacting with various endothelial cell surface receptors, including tyrosine kinase receptors, heparan-sulfate proteoglycans, and integrins.