Inhibition of Angiogenesis and Tumor Growth by SCH221153, a Dual {{alpha}}v{beta}3 and {{alpha}}v{beta}5 Integrin Receptor Antagonist

Tumor Biology

Inhibition of Angiogenesis and Tumor Growth by SCH221153, a Dual ${alpha}$ _vß₃ and ${alpha}$ _vß₅ Integrin Receptor Antagonist¹

C. Chandra Kumar², Michael Malkowski, Zizhang Yin, Elena Tanghetti, Bo Yaremko, Terry Nechuta, Judy Varner, Ming Liu, Elizabeth M. Smith, Bernie Neustadt, Marco Presta and Lydia Armstrong

Departments of Tumor Biology [C. C. K., M. M., Z. Y., B. Y., M. L., L. A.] and Medicinal Chemistry [T. N., E. M. S., B. N.], Schering-Plough Research Institute, Kenilworth, New Jersey 07033; Department of Biomedical Sciences and Biotechnology, School of Medicine, University of Brescia, 25123 Brescia, Italy [E. T., M. P.]; University of California, San Diego, California [J. V.]

New blood vessel formation is essential for tumor growth andmetastatic spread. Integrins ${alpha}$ _vß₃ and ${alpha}$ _vß₅are arginine-glycine-aspartic acid-dependent adhesion receptorsthat play a critical role in angiogenesis. Hence, selectivedual ${alpha}$ _vß₃ and ${alpha}$ _vß₅ antagonists may representa novel class of angiogenesis and tumor-growth inhibitors. Here,an arginine-glycine-aspartic acid-based peptidomimetic librarywas screened to identify ${alpha}$ _vß₃ antagonists. Selectedcompounds were then modified to generate potent and selectivedual inhibitors of ${alpha}$ _vß₃ and ${alpha}$ _vß₅ receptors.One of these compounds, SCH 221153, inhibited the binding ofechistatin to ${alpha}$ _vß₃ (IC₅₀ = 3.2 nM) and ${alpha}$ _vß₅(IC₅₀ = 1.7 nM) with similar potency. Its IC₅₀ values for related ${alpha}$ _IIbß₃ and ${alpha}$ ₅ß₁ receptors were 1294 nM and421 nM, respectively, indicating that SCH 221153 is highly selectivefor ${alpha}$ _vß₃ and ${alpha}$ _vß₅ receptors. In cell-basedassays, SCH 221153 inhibited the binding of echistatin to ${alpha}$ _vß₃-and ${alpha}$ _vß₅-expressing 293 cells and blocked the adhesionof endothelial cells to immobilized vitronectin and fibroblastgrowth factor 2 (FGF2). SCH 221153, but not the inactive analogueSCH 216687, was effective in inhibiting FGF2 and vascular endothelialgrowth factor-induced endothelial cell proliferation in vitrowith an IC₅₀ equal to 3–10 µM. Angiogenesis inducedby FGF2 in the chick chorioallantoic membrane assay was alsoinhibited by SCH 221153. Finally, SCH 221153 exerted a significantinhibition on tumor growth induced by intradermal or s.c. injectionof human melanoma LOX cells in severe combined immunodeficientmice.

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