New methods in genomics and chemistry technologies hold tremendous promise for impact on theprocess by which drugs are developed. Such impact, however, has yet to be realized, as these emergingmethods have yet to be integrated into a discovery effort. Furthermore, the capabilities themselves needto be further developed before they can be used routinely in the drug discovery process. We thereforepropose here to bring these capabilities together to create a new paradigm for drug discovery thatintegrates the disciplines of synthetic organic chemistry, cell biology, genomics and information science.While there is much activity in these individual areas, never before have they been synthesized andfocused in such a way as to> create a new conceptual framework for drug discovery. The goal of thiscomponent of the overall Broad IRC program is therefore to create the capabilities necessary for anintegrated 'pipeline' that can be applied to a wide range of applications and can be readily adopted bymany groups in both academia and industry.Specifically, in Aim 1 we will develop new approaches to cell-based high throughput screening based ongene expression signatures and high content imaging.
In Aim 2, we will leverage the power of DiversityOriented Synthesis (DOS) to create powerful small molecule libraries suitable for screening andsubsequent optimization.
In Aim 3, we will develop novel strategies for toxicogenomics with the goal ofusing this information to better prioritize lead compounds for subsequent testing in vivo.
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