As noted in the “Focus on Cardiovascular Disease” section of this edition of TherapeuticAdvances angiogenesis represents an emerging therapeutic target which by 2006, is expected to command a market of $1.75 billion. While stimulators of angiogenesis are receiving considerable attention due to their therapeutic potential in the context of conditions such as angina, myocardial infarction, peripheral vascular disease and stroke, inhibitors of angiogenesis have stolen the limelight due to there ability to limit tumor progression. While the development of molecules able to block the action of VEGF has led the field, those that inhibit fibroblast growth factors may also be of use in the clinic.

Acidic and basic fibroblast growth factors (aFGF and bFGF) are key angiogenesis-promoting polypeptides that belong to a larger family of mitogens, with similar biochemical and biological properties. FGFs are often detected in tumors and monoclonal antibodies or antisense oligonucleotides that block bFGF or FGF receptor-1 are able to inhibit angiogenesis and tumor progression. Furthermore, VEGF has been reported to require endogenous expression of bFGF in order to promote angiogenesis. FGFs show a characteristically high affinity for the glycosaminoglycan heparin and the glycosidic moiety of heparan sulfate proteoglycan and binding to either of these polysulfates is required for FGFs to recognize their specific tyrosine kinase receptor on the cell surface. Thus, disruption of the interaction of FGFs with heparin and heparan represents a candidate strategy for blocking angiogenesis. The development of small molecules would confer a significant advantage over many of the peptide-based therapeutics already in development.

Spanish researchers have recently exploited the observation that polysulfonated binaphthyl ureas known as suramins reduce angiogenic activity by disrupting the binding of the heparin binding sites of FGFs to their tyrosine kinase receptors to develop a series of novel small molecule inhibitors of angiogenesis. Likewise this group also exploited the findings that suradistas, non-cytotoxic synthetic binaphthalene sulfonic distamycin-A derivatives, tightly interact with FGFs, inhibit the binding of these polypeptides to the tyrosine kinase cell membrane receptors and suppress FGF-induced angiogenesis. Bringing these two bodies of data together, 1,3,6-naphthalenetrisulfonate (NTS) constitutes a minimal model for the inhibition of aFGF mitogenic activity by suramins and suradistas.

As part of their drug discovery strategy the Spanish group screened various naphthelenesulfonate derivatives for their ability to inhibit mitogenesis in vitro and angiogenesis in vivo and identified sodium 5-amino-2-naphthalenesulfonate (5-amino-2-NMS) as a molecule able to inhibit neovascularization at sub microgram/kg doses. The three-dimensional structure of the aFGF: 5-amino-2-NMS complex was then solved and it was found that binding occurs within a positively charged cavity present on the molecular surface of aFGF at a region corresponding to the heparin-binding site of aFGF. Several amino acid residues of aFGF that interact with heparin either establish contact with 5-amino-2-NMS or closely surround it. Five of those residues involved in the direct interaction with 5-amino-2-NMS have been described as essential for heparin binding. This study has therefore identified a novel lead for the treatment of conditions associated with angiogenensis and also provides a template for future molecular modeling approaches to design of further therapeutic candidates. Readers should be aware of LeadDiscovery’s PharmaceuticalSolutions service through which companies can have chemistry libraries docked into binding sites such as that described above.

Entry date Monday, April 28, 2003

Adapted from Fernandez-Tornero et al, J Biol Chem 2003 Apr 3; [epub ahead of print] - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk