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¹ Organic and Industrial Chemistry Department, Centre for Biomolecular Interdisciplinary Studies and Industrial Applications, University of Milan; ² Institute of Molecular Science and Technologies, Consiglio Nazionale delle Ricerche, Milan, Italy; ³ R&D Sigma-Tau S.p.A., Pomezia, Italy; ⁴ Institute of Pathology, Tor Vergata University, Rome, Italy; ⁵ Department of Human Anatomy and Histology, University of Bari Medical School, Bari, Italy; and ⁶ Unit of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, School of Medicine, University of Brescia, Brescia, Italy

Requests for reprints: Claudio Pisano, Area of Oncology, R&D Sigma-Tau S.p.A., Via Pontina km 30.400, 00040 Pomezia, Italy. Phone: 39-06-91-39-37-60; Fax: 39-06-91393988. E-mail: claudio.pisano{at}sigma-tau.it

The aim of the present study was to identify specific _vß₃/_vß₅ integrin antagonists active on tumor-induced angiogenesis. To this purpose, in vitro integrin-binding assays were used to screen a library of conformationally constrained bicyclic lactam Arg-Gly-Asp–containing pseudopeptides. The results identified ST1646 as a high-affinity specific ligand for _vß₃ and _vß₅ integrins with negligible interacting with ₅ß₁ integrin. In all the assays, ST1646 was equipotent to or more potent than the well-characterized integrin antagonists c(RGDfV) and cyclo(Arg-Gly-Asp-D-Phe-[NMe]Val) (EMD121974). In the chorioallantoic membrane assay, topical administration of ST1646 was able to prevent the angiogenic responses elicited by recombinant fibroblast growth factor-2 or vascular endothelial growth factor. In addition, systemic administration of ST1646 in mice exerted a significant antiangiogenic activity on neovascularization triggered by mammary carcinoma MDA-MB435 cells implanted s.c. in a dorsal air sac via a (Millipore Filter Corporation, Bedford, MA) chamber. Moreover, ST1646 delivery via an osmotic pump inhibited the growth and vascularization of tumor xenografts originating from the injection of _vß₃/_vß₅-expressing human ovarian carcinoma cells in nude mice. In agreement with the biochemical and pharmacologic studies, Monte Carlo/Stochastic Dynamics simulation showed that the bicyclic scaffold in ST1646 forced the compound to assume a preferred conformation superimposable to the X-ray conformation of _vß₃-bound EMD121974. Accordingly, computer-docking studies indicated that the ST1646-_vß₃ integrin complex maintains the ligand-receptor distances and interactions observed in the crystalline EMD121974-_vß₃ integrin complex. Taken together, these observations indicate that ST1646 represents a dual _vß₃/_vß₅ integrin antagonist with interesting biochemical and biological features to be tested in cancer therapy.

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Note: L. Belvisi and T. Riccioni contributed equally to this work.

Received 4/21/05; revised 7/28/05; accepted 8/30/05.