The ArrayPlate is a new microplate-based technology for measuring a profile of gene expression now being used for target validation, high throughput screening, and QSAR lead optimization. This Phase I grant proposes to demonstrate that the ArrayPlate, reconfigured into a slide format (ArraySlide), can provide an in vitro measure of toxicity and drug metabolism, generating highly reproducible (20% whole assay CV) and repeatable (day-to-day, lab-to-lab) quantitative data to which high powered statistical analysis can be applied as well as generating data on large numbers of compounds across a large number of cell lines and genes in a cost-effective manner. This grant represents the first attempt to apply this ArrayPlate technology to assess tox and drug metabolism. To validate the assay, compounds and cell lines have been selected to enable comparison to published literature. In addition, several hypotheses will be tested, including that by monitoring gene induction, the enzymes involved in drug metabolism can be profiled; that drug mediated gone expression can be related to tox; that by measuring gene expression across a variety of cell lines, time points, and doses, the degree of induction will be sufficiently quantitative and repeatable to enable comparison of drugs and provide the type of data required for use of the in vitro assay as a QSAR tox/metabolism optimization data and will contain the relevant published literature and statistical analysis routines for data analysis. A follow-on Phase II program will extend the number of compounds tested, including close analogs, develop a related in vivo ArraySlide assay, and validate use as a cost effective and powerful new experimental tox/metabolism profiling and QSAR optimization strategy. Such a strategy leverages the power of genomics to produce higher quality clinical candidates and backups optimized and differentiated experimentally for tox/metabolism and could reduce the number of and change the role of animals used in tox and metabolism testing to confirmatory rather than exploratory.
