) The objective of the Cell Fluorescent Biosensor Core (Core E) is to provide primary, multiparameter, cellular, high throughput systems (HTS) for the Projects and Core A described in this NCDDG application. The key instrument is a Cellomics Array Scan, which will also provide a important link between compound sources (namely the NCI compound library and the compounds from the Combinatorial Chemistry Core A) and all of the target screening activities directed toward identifying cancer therapies. There has been an explosive growth in our understanding of the human genome, which has radically enhanced the number of molecular targets for potentially efficacious pharmacological entities. Many potential interesting molecular targets are regulated not only by expression levels but also by their subcellular or spatial localization. Agents that selectively affect the spatial localization of cancer related molecular targets have not been carefully investigated. The underlying hypothesis upon which work by Core E is based is that identifying agents that affect the translocation of cancer-related proteins will yield small molecules with unique potential as anticancer drugs. To achieve this goal in a timely manner, we have incorporated robotic-based, multiparametric, detection systems that will permit rapid evaluation of newly identified biological targets and synthesized chemical entities in intact living cells.
The aims of the Core service are: 1) To identify compounds having significant effects on the spatial location of targeted cell cycle progression and apoptosis-associated proteins, 2) To identify compounds having significant effects on apoptosis, 3) To determine the optimal drug concentration for prioritized compounds and, 4) To determine if prioritized agents have synergistic or antagonist effects with representative conventional anticancer drugs.
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