University of Kansas Specialized Chemistry Center

描述(由申请人提供)：堪萨斯大学(KU)在合成药物化学方面有成功的历史，一直延续到今天。NIH在这些活动中的投资包括一个化学方法和图书馆开发(CMLD)中心和一个试点规模图书馆赠款。在强有力的机构支持下，包括一座专门用于探测器发现的新建筑，我们建议将这些资源整合起来，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个候选探测器集合，每组包含100-300个离散化合物，数量为20毫克，通过高效液相色谱(UV或ESL检测)确定化学纯度为90%。在过去的15个月里，我们向MLSCN提交了1600多种符合这些要求的化合物，包括大约12种不同的化学类型。因此，我们已经在与SCC倡议所需的水平相当的水平上运作，并制定了一项现实的计划，以迅速应对从MLPCN伙伴关系中获得的优化HITS的挑战。拟议计划的优势包括(1)证明有能力生产符合MLPCN要求的数量和纯度的小分子；(2)如何将化合物有效地送到生物合作者手中的实用技术，(3)在与生物合作者合作以及优化先导化合物的化合物效力和选择性方面的专业知识(以及每月提供指导的一批杰出的顾问)，(4)并行合成技术的实践经验和图书馆生产的优秀基础设施，(5)分配给一个全新的实验室，该实验室在一个致力于合作生物医学发现的新建筑扩建部分中有11个引擎盖(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和将促进协调项目活动的现有行政结构；(8)为SCC提供必要的主要设备和建立必要的实验室的配套资金；(9)对MLSCN的明确承诺。 一个以中心为基础的研究项目被提出来解决小分子探针的细胞内目标识别的问题，这是生物医学研究中公认的障碍。该项目的目标将是(1)开发使用荧光分子探针可视化和识别细胞内蛋白质靶标的方法，以及(2)开发酵母三杂交(Y3H)系统作为识别小分子蛋白质靶标的工具。

DESCRIPTION (provided by applicant): 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.