Leads for development of new naphthalenesulfonate derivatives with enhanced antiangiogenic activity: crystal structure of acidic fibroblast growth factor in complex with 5-amino-2-naphthalene sulfonate.
Inhibition of angiogenesis-promoting factors such as fibroblast growth factors is considered to be a potential procedure for inhibiting solid tumor growth. Although several peptide-based inhibitors are currently under study, the development of antiangiogenic compounds of small molecular size is a pharmacological goal of considerable interest. We have already shown that certain naphthalene sulfonates constitute minimal functional substitutes of the antiangiogenic compounds of the suramin and suradista family. Using those data as a lead, we have carried out a rational search for new angiogenesis inhibitors that could provide new pharmacological insights for the development of antiangiogenic treatments. The results of the study strongly underline the relevance of the stereochemistry for an efficient inhibition of acidic fibroblast growth factor mitogenic activity by the naphthalene sulfonate family and allow us to formulate rules to aid in searching for new inhibitors and pharmaceutical developments. To provide further leads for such developments and acquire a detailed insight into the basis of the inhibitory activity of the naphthalene sulfonate derivatives, we solved the three-dimensional structure of acidic fibroblast growth factor complexed to 5-amino-2-naphthalenesulfonate, the most pharmacologically promising of the identified inhibitors. The structure shows that binding of this compound would hamper the interaction of acidic fibroblast growth factor with the different components of the cell membrane mitogenesis-triggering complex.
Fernández-Tornero
Carlos
C
Departamento de Estructura y Función de Proteínas, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, C/Velázquez 144, 28006 Madrid, Spain.
Lozano
Rosa M
RM
Redondo-Horcajo
Mariano
M
Gómez
Ana M
AM
López
José C
JC
Quesada
Ernesto
E
Uriel
Clara
C
Valverde
Serafín
S
Cuevas
Pedro
P
Romero
Antonio
A
Giménez-Gallego
Guillermo
G
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D016220:Fibroblast Growth Factor 1 / Q000737:chemistry* / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D009282:Naphthalenesulfonates / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D012964:Sodium / Q000494:pharmacology
C475668:5-amino-2-naphthalenesulfonate; D020533:Angiogenesis Inhibitors; D009282:Naphthalenesulfonates; D016220:Fibroblast Growth Factor 1; D006493:Heparin; D012964:Sodium