Despite huge advances in our understanding of the molecular mechanisms that drive the neoplastic process, the mainstays of cancer therapy have changes relatively little. New sources of small molecules are required to counter the alterations in protein function that occur as a result of the mutations that give rise to cancer. We therefore need general strategies that can identify small molecules that activate or inhibit the function of specific proteins. Accomplishing this goal is the central mission of the newly-formed Harvard Institute of Chemistry and Cell Biology (ICCB): to develop general methods for creating cell-permeable small molecules that can be used to manipulate the function of any given protein target. By developing a system that makes this process routine, we aim to exploit the tools of chemistry to generate a powerful interface between genomics, biology and medicine. In this Program Project, we will develop new chemistry and screening technologies, and apply these to biological assays relevant to cancer. In Project 1, we will use the full ranges of modern synthetic methods combined the split-pool synthesis strategy to produce large combinatorial libraries of small molecules that have natural-product-like structures. In Project 2, we will develop a high-throughput, nanoliter-volume screening format that will enable us to screen these libraries. We will also develop a general method for small-molecule-dependent genetic selections in yeast, and a general approach to identification of the protein targets of small molecules. In Project 3, we will create a range of """"""""smart assays"""""""" relevant to cancer that seek to identify inhibitors of proteins involved in cell cycle control, cytoskeleton function and DNA repair. The elements of this Program Project are highly interrelated. The assays developed in Project 3 will make use of the new screening formats developed in Project 2, and will be used to screen the libraries made in Project 1. The Synthetic Chemistry Core will supply monomers to Project 1 for library synthesis, and will resynthesize compounds discovered in the screens performed in Projects 2 and 3 for further study. The Synthetic Chemistry Core will also synthesize small libraries focused on the identified leads for analysis of structure-activity relationships. The Administrative Core will coordinate both the scientific efforts and the budget management of the research teams.
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