HIGH-CONTENT SCREENING - A NEW APPROACH TO EASING KEY BOTTLENECKS IN THE DRUG DISCOVERY PROCESS

Recent improvements in target discovery and high throughput screening (HTS) have increased the pressure at key points along the drug discove ry pipeline. High-content screening (HCS) was developed to ease bottle necks that have formed at target validation and lead optimization poin ts in the pipeline. HCS defines the role of targets in cell functions by combining fluorescence-based reagents with the ArrayScan((TM)) Syst em to automatically extract temporal and spatial information about tar get activities within cells. The ArrayScan System is a tabletop instru ment that includes optics for subcellular resolution of fluorescence s ignals from many cells in a field within a well of a microtiter plate. One demonstrated application is a high-content screen designed to mea sure the drug-induced transport of a green fluorescent protein-human g lucocorticoid receptor chimeric protein from the cytoplasm to the nucl eus of human tumor cells. A high-content screen is also described for the multiparametric measurement of apoptosis. This single screen provi des measurements of nuclear size and shape changes, nuclear DNA conten t, mitochondrial potential, and actin-cytoskeletal rearrangements duri ng drug-induced programmed cell death. The next generation HCS system is a miniaturized screening platform, the CellChip((TM)) System, that will increase the throughput of HCS, while integrating HCS with HTS on the same platform.