Inhibition of Angiogenesis and Tumor Growth by SCH221153, a Dual αvβ3 and αvβ5 Integrin Receptor Antagonist

New blood vessel formation is essential for tumor growth and metastatic spread. Integrins αvβ3 and αvβ5 are arginine-glycine-aspartic acid-dependent adhesion receptors that play a critical role in angiogenesis. Hence, selective dual αvβ3 and αvβ5 antagonists may represent a novel class of angiogenesis and tumor-growth inhibitors. Here, an arginine-glycine-aspartic acid-based peptidomimetic library was screened to identify αvβ3 antagonists. Selected compounds were then modified to generate potent and selective dual inhibitors of αvβ3 and αvβ5 receptors. One of these compounds, SCH 221153, inhibited the binding of echistatin to αvβ3 (IC50 = 3.2 nm) and αvβ5 (IC50 = 1.7 nm) with similar potency. Its IC50 values for related αIIbβ3 and α5β1 receptors were 1294 nm and 421 nm, respectively, indicating that SCH 221153 is highly selective for αvβ3 and αvβ5 receptors. In cell-based assays, SCH 221153 inhibited the binding of echistatin to αvβ3- and αvβ5-expressing 293 cells and blocked the adhesion of endothelial cells to immobilized vitronectin and fibroblast growth factor 2 (FGF2). SCH 221153, but not the inactive analogue SCH 216687, was effective in inhibiting FGF2 and vascular endothelial growth factor-induced endothelial cell proliferation in vitro with an IC50 equal to 3–10 μm. Angiogenesis induced by FGF2 in the chick chorioallantoic membrane assay was also inhibited by SCH 221153. Finally, SCH 221153 exerted a significant inhibition on tumor growth induced by intradermal or s.c. injection of human melanoma LOX cells in severe combined immunodeficient mice.