Recent advances in our understanding of the mechanisms of carcinogenesis are leading to the discovery and synthesis of new drugs that can inhibit tumor development in both experimental animals and humans. The discovery and development of both natural and synthetic chemopreventive agents is rapidly advancing because screening methods are now focusing on specific molecular targets that are involved directly in carcinogenesis, and structure-based design and optimization of lead compounds is maturing as a field. One of the long-term objectives of this program proposal is to use target-based approaches to identify novel chemopreventive compounds that will serve either directly as therapeutic agents, or as lead molecules for the structure-based design and synthesis of potential therapeutic agents. To attain this objective, we propose a series of specific aims that have the unifying theme of investigating at the molecular level, the structural basis for chemopreventive activity of natural and synthetic compounds. Specifically, we propose to clone, express, purify, crystallize, and determine the x-ray structures of select molecular targets in complex with either new and/or existing chemopreventive compounds. Initial targets include those already under investigation by our program, i.e. cyclooxygenases 1 and 2 and estrogen receptors alpha and beta, as well as new targets including the Keap1/Nrf2 system, and the retinoid and androgen receptors. The threedimensional structures of active compounds, in complex with the protein targets will be determined and the structural information obtained will be used to help guide the synthetic efforts for the design of novel and more potent chemopreventive agents. In addition to the proposed studies on the macromolecular targets. This project will also serve partially as a core that will provide purified protein for bioassay-guided fractionation and compound identification. Finally, we will also determine the small molecule structures of natural and synthetic compounds.
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