Dysregulation of normal programmed cell death mechanisms plays an essential role in the pathogenesis of most tumors, extending the lifespan of neoplastic cells and allowing them to tolerate the accumulation of additional genetic hits that would otherwise induce apoptosis. Resistance to programmed cell death also results in a multidrug chemoresistance and radioresistance phenotype. In recent years, a number of apoptosis regulating proteins and genes have been discovered, thus creating novel potential targets for drug discovery. The purpose of this proposal is to develop high through-put assays based on appropriate apoptosis-regulatory protein and gene targets. The approaches will include a combination of in vitro protein-protein interaction and cell-based assays. The drug targets include (1) proteins that interact with the cytosolic domains of particular Tumor Necrosis Factor (TNF) family receptors, and (2) members of the Bcl-2 family of apoptosis-regulating proteins and genes. Diverse libraries of small molecule compounds will be screened in collaboration with other investigators associated with the program. Candidate molecules will then be further characterized in low through-put secondary assays for activity against their intended molecular targets in human tumor cell lines, and promising compounds advanced into xenograph tumor studies in mice. These lead compounds can then serve as the starting point for extensive structure-activity relation (SAR) studies, designed to ultimately produce new therapeutics targeted against novel targets for cancer.
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