Disruption of matrix metalloproteinase 2 binding to integrin αvβ3 by an organic molecule inhibits angiogenesis and tumor growth in vivo

Matrix metalloproteinase 2 (MMP2) can associate with integrin alpha (nu)beta (3) on the surface of endothelial cells, thereby promoting vascular invasion. Here, we describe an organic molecule (TSRI265) selected for its ability to bind to integrin alpha (nu)beta (3) and block alpha (nu)beta (3) interaction with MMP2. Although disrupting alpha (nu)beta (3)/MMP2 complex formation, TSRI265 has no effect on alpha (nu)beta (3) binding to its extracellular matrix ligand vitronectin and does not influence MMP2 activation or catalytic activity directly. However, TSRI265 acts as a potent antiangiogenic agent and thereby blocks tumor growth in vivo. These findings suggest that activated MMP2 does not facilitate vascular invasion during angiogenesis unless it forms a complex with alpha (nu)beta (3) on the endothelial cell surface. By disrupting endothelial cell invasion without broadly suppressing cell adhesion or MMP function, the use of compounds such as TSR1265 may provide a novel therapeutic approach for diseases associated with uncontrolled angiogenesis.