The University of Kansas (KU) has a history of success in synthetic medicinal chemistry that continues to the present day. NIH investments in these activities have included a Chemical Methodologies and Library Development (CMLD) center and a Pilot Scale Library grant. With strong institutional support including a new building dedicated to probe discovery, we propose to marshal these resources in the service of the MLPCN as a Specialized Chemistry Center (SCC). The goals of the KU SCC will be to synthesize 10-15 collections of probe candidates per year, with each set containing between 100-300 discrete compounds in 20 mg quantities and >90% chemical purity as determined by HPLC (UV or ESL detection). In the past 15 months, we submitted over 1600 compounds that met these requirements to the MLSCN, comprising about a dozen different chemotypes. Thus, we are already functioning at the level comparable to that required for the SCC initiative and have developed a realistic plan for quickly undertaking the challenge of optimizing hits obtained from the MLPCN partnership. Strengths of the proposed program include (1) the demonstrated capability of producing small molecules in the quantities and purities demanded by MLPCN;(2) practical know-how of how to get compounds efficiently into the hands of biological collaborators, (3) demonstrated expertise in working with biological collaborators and optimizing compound potency and selectivity of a lead compound (and an outstanding set of consultants who will provide guidance on a monthly basis), (4) practical experience with parallel synthesis techniques and outstanding infrastructure for library production, (5) assignment to a brand-new laboratory containing 11 hoods in a new building extension that is dedicated to collaborative biomedical discovery (labs to be completed in 4/08), (6) strong cheminformatics expertise, (7) an experienced PI and an existing administrative structure that will facilitate the coordination of the project activities, (8) matching funds to provide essential major equipment and set up necessary laboratories for the SCC, and (9) a demonstrated commitment to the MLSCN. A Center-based research project is proposed to address the question of intracellular target identification for small molecule probes, an acknowledged roadblock in biomedical research. The goals of this project will be to (1) develop methodology for visualizing and identifying intracellular protein targets using fluorescent molecular probes and (2) develop yeast three-hybrid (Y3H) systems as tools for the identification of protein targets of small molecules.
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