University of Kansas Specialized Chemistry Center

堪萨斯大学（KU）在合成药物化学方面的成功历史一直延续到今天。美国国立卫生研究院对这些活动的投资包括化学方法和图书馆发展（CMLD）中心和试点规模图书馆赠款。在强有力的机构支持下，包括一个专门用于探针发现的新大楼，我们建议将这些资源作为一个专门的化学中心（SCC）为MLPCN服务。KU SCC的目标是每年合成10-15个候选探针集合，每个集合含有100-300个独立的化合物，数量为20毫克，化学纯度为90 - 90%，通过HPLC （UV或ESL检测）确定。在过去的15个月里，我们向MLSCN提交了超过1600种符合这些要求的化合物，包括大约12种不同的化学型。因此，我们已经在与SCC倡议所需的水平相当的水平上运作，并制定了一个现实的计划，以迅速承担优化从MLPCN合作伙伴关系中获得的点击量的挑战。该计划的优势包括：(1)具有生产MLPCN所需数量和纯度的小分子的能力；(2)如何有效地将化合物送到生物合作者手中的实际知识；(3)在与生物合作者合作和优化化合物效力和先导化合物选择性方面表现出专业知识（以及一组优秀的顾问，他们将每月提供指导）；(4)平行合成技术的实践经验和优秀的库生产基础设施；(5)分配到一个全新的实验室，在一个新的建筑扩建中，包含11个专门用于协作生物医学发现的实验室（实验室将于2008年4月完成），(6)强大的化学信息学专业知识，(7)经验丰富的PI和现有的行政结构，将促进项目活动的协调，(8)匹配资金，为SCC提供必要的主要设备和建立必要的实验室，(9)对MLSCN的承诺。

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.