Large-scale unbiased profiling technologies, such as genomics and proteomics, offer a powerful means to gain insights into the mechanism of action of bioactive small-molecules. These technologies can provide a global and relatively unbiased view of the molecular changes induced in cells and tissues by pharmacological agents. These changes can in turn identify cellular pathways that are directly or indirectly affected by a compound of interest, thereby unveiling previously unappreciated functions for the corresponding protein target. Moreover, as we have found in our preliminary studies, genomic and proteomic methods can even discriminate unexpected differences in the pathway effects of molecular probes that target the same protein [1]. With these considerations in mind, we have set as a major goal of the TSRI Center- Based Initiative (CBI) to develop a suite of advanced genomic and proteomic technologies that can be generally applied to annotate the mechanism of action of POC probes developed by the MPLCN. We propose three specific long-term projects, each of which will be presented in the context of its Background & Significance. Because of space limitations, preliminary data is discussed largely by reference, within the Research Design and Methods for each specific Aim. Each Project is led by a senior faculty of national and international standing. The projects and their respective leaders are: 1: Functional and Structural Genomic Approaches to Small Molecule Discovery (Patrick Griffin). 2: Proteomic Pathway Mapping to Probe Small-Molecule Mechanism-of-Action (John R Yates III) 3: Advanced Enzyme Profiling (Benjamin Cravatt).
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