Identification of a novel class of small-molecule antiangiogenic agents through the screening of combinatorial libraries which function by inhibitingthe binding and localization of proteinase MMP2 to integrin alpha(v)beta(3)

The process of new blood vessel growth from existing vasculature, known as angiogenesis, is critical to several pathological conditions, most notably cancer. Both MMP2, which degrades the extracellular matrix (ECM), and integ rin alpha (v)beta (3), which contributes to endothelial cell attachment to the ECM, are critically involved in this process. Recent findings have show n that MMP2 is localized in an active form on the surface of invasive endot helial cells based on its ability to directly bind integrin alpha (v)beta ( 3), suggesting that disrupting this protein-protein interaction may represe nt a new target for the development of angiogenesis inhibitors. The screeni ng of small molecule libraries led to the identification of compounds which disrupt the MMP2-alpha (v)beta (3) interaction in an in vitro binding assa y. A prototypical inhibitor was further found to prevent the degradation of the protein matrix without directly inhibiting MMP2 activity or disrupting the binding of alpha (v)beta (3) to its classical ECM ligand, vitronectin. The synthesis and screening of analogues and substructures of this lead co mpound allowed the identification of requisite structural features for inhi bition of MMP2 binding to alpha (v)beta (3) This led to the synthesis of a more water-soluble derivative which maintains the in vitro biological prope rties and has potent antiangiogenic and antitumor activity in vivo, validat ing the target as one useful for therapeutic intervention.