Disruption of matrix metalloproteinase 2 binding to integrin alpha vbeta 3 by an organic molecule inhibits angiogenesis and tumor growth in vivo.
Matrix metalloproteinase 2 (MMP2) can associate with integrin alpha(v)beta3 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 alphav(v)beta3 and block alpha(v)beta3 interaction with MMP2. Although disrupting alpha(v)beta3/MMP2 complex formation, TSRI265 has no effect on alpha(v)beta3 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(v)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 TSRI265 may provide a novel therapeutic approach for diseases associated with uncontrolled angiogenesis.
Silletti
S
S
Department of Immunology and Vascular Biology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Kessler
T
T
Goldberg
J
J
Boger
D L
DL
Cheresh
D A
DA
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002642:Chick Embryo; D002823:Chorion / Q000098:blood supply / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D006224:Cricetinae; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D006651:Histocytochemistry; D015151:Immunoblotting; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D008545:Melanoma / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D019096:Vitronectin / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D061965:Matrix Metalloproteinase Inhibitors; D009842:Oligopeptides; D019030:Receptors, Vitronectin; C423566:TSR1265; D019096:Vitronectin; C047981:arginyl-glycyl-aspartic acid; D003094:Collagen; D020778:Matrix Metalloproteinase 2