Author/Authors :
Schimmer، نويسنده , , Aaron D. and Welsh، نويسنده , , Kate and Pinilla، نويسنده , , Clemencia and Wang، نويسنده , , Zhiliang and Krajewska، نويسنده , , Maryla and Bonneau، نويسنده , , Marie-Josee and Pedersen، نويسنده , , Irene M. and Kitada، نويسنده , , Shinichi and Scott، نويسنده , , Fiona L. and Bailly-Maitre، نويسنده , , Beatrice and Glinsky، نويسنده , , Gennadi and Scudiero، نويسنده , , Dominick and Sausville، نويسنده , , Edward and Salvesen، نويسنده , , Guy and Nefzi، نويسنده , , Adel and Ostresh، نويسنده , , John M. and Houghten، نويسنده , , Richard A. and Reed، نويسنده , , John C.، نويسنده ,
Abstract :
Apoptosis resistance commonly occurs in cancers, preventing activation of Caspase family cell death proteases. XIAP is an endogenous inhibitor of Caspases overexpressed in many cancers. We developed an enzyme derepression assay, based on overcoming XIAP-mediated suppression of Caspase-3, and screened mixture-based combinatorial chemical libraries for compounds that reversed XIAP-mediated inhibition of Caspase-3, identifying a class of polyphenylureas with XIAP-inhibitory activity. These compounds, but not inactive structural analogs, stimulated increases in Caspase activity, directly induced apoptosis of many types of tumor cell lines in culture, and sensitized cancer cells to chemotherapeutic drugs. Active compounds also suppressed growth of established tumors in xenograft models in mice, while displaying little toxicity to normal tissues. These findings validate IAPs as targets for cancer drug discovery.
