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A Peptidomimetic Antagonist of the Integrin _vß₃ Inhibits Leydig Cell Tumor Growth and the Development of Hypercalcemia of Malignancy

Departments of Discovery Pharmacology [C. P. C., D. M. M., J. A. P., M. A. N., S. L. S., W. F. W., G. A. N.], Oncology [V. W. E.], and Medicinal Chemistry [P. G. R.], G. D. Searle Research and Development, Monsanto Company, St. Louis, Missouri 63198

The integrin _vß₃ interacts with the arginine-glycine-aspartic acid (RGD) tripeptide recognition sequence of a variety of extracellular matrix proteins. Recent studies show that _vß₃ plays an important role in tumor-induced angiogenesis and tumor growth and that antagonists of _vß₃ inhibit angiogenic processes that include endothelial cell adhesion and migration. Consequently, we reasoned that an RGD-based peptidomimetic antagonist of _vß₃ might inhibit tumor angiogenesis and tumor growth in vivo. An RGD-peptidomimetic library was screened to identify antagonists of vitronectin binding to _vß₃, and the compounds chosen were modified to produce selective and potent inhibitors of _vß₃. One of these compounds, ß-[[2-2-[[[3-[(aminoiminomethyl)amino]-phenyl]carbonyl]amino]acetyl]amino]-

3,5-dichlorobenzenepropanoic acid (SC-68448), inhibited vitronectin binding to both _vß₃ and the closely related platelet receptor, _IIbß₃, in a dose-responsive manner. SC-68448 inhibited vitronectin binding to _vß₃ (IC₅₀, 1 nM) and fibrinogen binding to the platelet receptor _IIbß₃ (IC₅₀, >100 nM), demonstrating that SC-68448 was 100-fold more potent as an inhibitor of _vß₃ versus _IIbß₃. In cell-based studies, SC-68448 inhibited _vß₃-mediated endothelial cell proliferation in a dose-dependent manner but did not inhibit tumor cell proliferation, suggesting that effects on endothelial cell proliferation were not due to SC-68448-induced cytotoxicity. In accord with these results, SC-68448 inhibited angiogenesis in vivo in a basic fibroblast growth factor-induced rat corneal neovascularization model. A xenogeneic severe combined immune deficiency mouse/rat Leydig cell tumor model was developed for testing SC-68448 as an inhibitor of tumor growth in vivo. Rat Leydig cell tumors grew rapidly in severe combined immune deficiency mice and produced humoral hypercalcemia of malignancy. SC-68448 inhibited the growth of the tumors in mice by up to 80% and completely blocked the development of hypercalcemia. Together, these results demonstrate the feasibility of antitumor therapies based upon the development of nontoxic small molecule pharmacological antagonists of integrin _vß₃.

¹ To whom requests for reprints should be addressed, at Monsanto Company, AA3C, Searle Research and Development, 700 Chesterfield Village Parkway, St. Louis, MO 63198. Phone: (314) 737-6847; Fax: (314) 737-7310; E-mail: cpcarr@monsanto.com.

Received 12/18/97. Accepted 3/18/98.

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