Discovery of small molecule integrin αvβ3 antagonists as novel anticancer agents

Integrin alpha(v)beta(3) has been implicated in multiple aspects of tumor progression and metastasis. Many tumors have high expression of alpha(v)beta(3) that correlates with tumor progression. Therefore, alpha(v)beta(3) receptor is an excellent target for drug design and delivery. We have discovered a series of novel alpha(v)beta(3) antagonists utilizing common feature pharmacophore models. Upon validation using a database of known alpha(v)beta(3) receptor antagonists, a highly discriminative pharmacophore model was used as a 3D query. A search of a database of 600 000 compounds using the pharmacophore Hypo5 yielded 832 compounds. On the basis of structural novelty, 29 compounds were tested in alpha(v)beta(3) receptor specific binding assay and four compounds showed excellent binding affinity. A limited SAR analysis on the active compound 26 resulted in the discovery of two compounds with nanomolar to subnanomolar binding affinity. These small-molecule compounds could be conjugated to paclitaxel for selective delivery to alpha(v)beta(3) positive metastatic cancer cells.