integrin alphaVbeta3-targeted small molecule-drug conjugate VIP236

A small molecule-drug conjugate (SMDC) composed of an integrin alphaVbeta3 binder conjugated, via a cleavable linker, to a camptothecin-based topoisomerase I inhibitor, with potential antineoplastic activity. Upon administration of integrin alphaVbeta3-targeted SMDC VIP236, the integrin alphaVbeta3 binder targets and binds to integrin alphaVbeta3 expressed on tumor cells and tumor vessel endothelial cells. Upon binding and linker cleavage by neutrophil elastase in the tumor microenvironment (TME), the camptothecin-based topoisomerase I inhibitor is released. The topoisomerase I inhibitor inhibits DNA topoisomerase I activity, thereby inhibiting DNA replication and generating DNA single- and double-strand breaks, and leading to cell cycle arrest and apoptosis. This inhibits the proliferation of integrin alphaVbeta3-expressing tumor cells, angiogenesis and metastasis. Integrin alphaVbeta3, a cell adhesion and signaling receptor, is overexpressed on the surface of tumor vessel endothelial cells, some tumor cells, and a number of other cell types.