The Comprehensive Center for Chemical Probe Discovery and Optimization at Scripps

斯克里普斯化学探针发现和优化综合中心

• 批准号: 7682882
• 负责人: HUGH ROSEN
• 金额: $ 1513.98万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7682882
• 关键词: Comprehensive; Center; Chemical; Probe; Discovery

DESCRIPTION (provided by applicant): The goal of the MLPCN is to integrate high-throughput chemical approaches with state-of-the art genetics, (cellular, molecular and in vivo biology in a multi-disciplinary effort to discover of proof-of-concept (POC) molecular probes for cell and in vivo systems. Probes help transform biomedical advances to impact on public health and quality of life. Production capacity at The Scripps Center in the pilot MLSCN phase was demonstrated by publishing >68 assays in PUBCHEM, optimizing POC probes for 5 molecular targets and peer-reviewed publication of probes with low nanomolar potency, selectivity, and in vivo efficacy, to define novel biological and therapeutic targets. The Center sustained full production capabilities for assay development and for ?HTS implementation in 1536-well format (>20/year). >80 data sets were published in PUBCHEM at a rate of 2 full library assays/month. In the past 12 months alone, 27 ?HTS campaigns including 20 primary cell-based screens) for 18 molecular targets in 8 different target classes, using 8 detection formats (and from 13 external PIs) published. Internal discovery projects were screened on a single compound library of >600,000, exceeding MLPCN requirements. These data were achieved in well volumes (of 5-10 ?l at low cost. The Center spares NIH compound collection and controls cost using 2 ?l of compound (solution per year for 24 primary screens, and requiring only 5 ?l for hit-picks, reconfirmation and 10 point titrations. Formats include ion flux and GPCR assays, reporter gene, transcription factor and nuclear receptor assays, enzyme assays, protein-protein and protein-RNA interactions and phenotypic screens. The Center currently supports hit-to-probe chemical synthesis across 8 projects/year by resynthesis, chemi-informatics, medicinal chemistry, secondary and specificity assay implementation and screening pharmacokinetics/ metabolism studies for efficient probe optimization. The Center developed novel technologies for high throughput selectivity profiling across gene families and enzymes for optimizing target-selective probes. This Comprehensive Center supports production discovery of POC probes for most target classes by meeting 3 (Aims. 1: Develop 25 assays/year to HTS readiness. 2: Implement 25 ?HTS screens/year at 300-500,000 individual compounds and publish quality-assured data to PUBCHEM. 3: Optimize screening hits to probes or POC in cells and/or in vivo for 10-15 programs/year. The Center provides public data, tools and resources hat enhance the success of NIH Roadmap and impact on human health.

描述（由申请人提供）： MLPCN的目的是将高通量化学方法与最先进的遗传学（细胞，分子和体内生物学中的最新遗传学结合在一起，以发现概念证明（POC）分子探险（POC）分子探险（POC）的分子探针（POC）的体内系统。通过在Pubchem进行> 68个测定法，对POC进行了5个分子靶标的和同行评审的探针，这些探针具有低纳摩尔效力，选择性和体内功效，以定义新的生物学和治疗靶标的全部生产能力。仅在过去的12个月中以2个完整的图书馆测定速度出版，其中27个hts运动，包括20个基于细胞的筛选），使用8个不同的目标类别中的18个分子目标，使用8种检测格式（来自13个外部PIS）。内部发现项目在一个> 600,000的单个复合库中进行了筛选，超出了MLPCN要求。 These data were achieved in well volumes (of 5-10 ?l at low cost. The Center spares NIH compound collection and controls cost using 2 ?l of compound (solution per year for 24 primary screens, and requiring only 5 ?l for hit-picks, reconfirmation and 10 point titrations. Formats include ion flux and GPCR assays, reporter gene, transcription factor and nuclear receptor assays, enzyme assays, protein-protein蛋白质 - RNA相互作用和表型筛选目前，通过重新合成，化学中的化学，药物化学，次要化学和特异性测定法，并筛选有效的探测范围的高度探测范围，以实现高度优化的高度探测性，并筛选了8个项目/年的探针化学合成。探针这个全面的中心通过遇到3个目标，支持大多数目标类别的POC探针（Aims）。 1：为HTS准备就绪开发25种测定。 2：以300-500,000个单独的化合物（将质量保存的数据发布到PubChem）实施25张HTS屏幕/年。 3：以10-15个程序/年，优化细胞和/或体内探针或POC的筛选。该中心提供公共数据，工具和资源帽子增强了NIH路线图的成功和对人类健康的影响。