Natural and synthetic inhibitors of FGF-dependent angiogenesis for tumor targeted therapies (DCM.AD007.151)

Thematic area

Chemical sciences and materials technology

Project area

Structure responsible for the research project

Istituto di Scienze e Tecnologie Chimiche "Giulio Natta" (SCITEC)

Project manager

LAURAGIUDITTA RAGONA
Phone number: 0223699619
Email: laura.ragona@scitec.cnr.it

Abstract

Fibroblast growth factor (FGF)/Fibroblast growth factor Receptor (FGFR) signalling pathways regulate cell proliferation, angiogenesis and are recognized therapeutic targets for a wide array of pathologies, including angiogenesis-driven diseases and cancer.
To date, several FGFR specific inhibitors have been developed (TKI inhibitors, antibodies and extracellular allosteric inhibitors of FGFR). A drug design approach, combining MD, NMR and biological data, allowed us to design and select small molecules, mimicking the function of the endogenous protein inhibitors thrombospondin-1 and pentraxin-3. These molecules specifically targeted FGF2 with effects on the stability of the whole FGF2/FGFR/HSPG ternary complex (Foglieni et al, 2016; Pagano et al, 2012) and showed anti-cancer efficiency in vitro and in vivo. We recently investigated the ability of natural products to target the FGF/FGFR system. A detailed molecular level description can be derived by NMR and docking studies. Cellular studies on FGF2-induced endothelial cells proliferation and FGFR phosphorylation complement the spectroscopic results and validate the proposed mechanism of antiangiogenic action.

Goals

Identification of antiangiogenic molecules
Description of the molecular mechanism of action
Design of new synthetic inhibitors

Start date of activity

01/07/2020

Keywords

NMR, angiogenesis, drug discovery

Last update: 21/04/2025