Survivin is the smallest member of the inhibitor of apoptosis (IAP) family containing a single baculovirus IAP repeat (BIR) domain and a long c-terminal ?-helix. Survivin is virtually undetectable in non-proliferating human tissues and is only expressed during the G2/M phase of the cell cycle. In cancerous tissues, however, Survivin is constitutively overexpressed, independent of the cell cycle, and has been shown to impart resistance to apoptosis-inducing anticancer treatments. Besides being a chromosomal passenger protein, there is mounting evidence that Survivin is also an inhibitor of caspases, the family of cysteine proteases responsible for mediating apoptosis. We are currently using a structure-based-design approach to identify and develop both small molecule peptide- and non-peptide derived ligands of Survivin for the purpose of antagonizing Survivinís inhibition of caspase activity. This project relies on computational modeling and virtual screening of compound libraries in addition to synthetic organic chemistry and biochemical screening and characterization of compounds. Among some of the routine biochemical assays used are caspase functional assays and fluorescence polarization binding assays. Ultimately, we hope to identify potential small molecule therapeutic agents that can antagonize Survivinís anti-apoptotic effects in cancer tissues, and thereby resensitize resistant tumors to preexisting anti-cancer treatments.