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: 8538719
• 负责人: HUGH ROSEN
• 金额: $ 569.26万
• 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/8538719
• 关键词: Comprehensive; Center; Chemical; Probe; Discovery

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 uHTS 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 uHTS 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 ul at low cost. The Center spares NIH compound collection and controls cost using 2 ul of compound (solution per year for 24 primary screens, and requiring only 5 ul 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 uHTS 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.

MLPCN的目标是将高通量化学方法与最先进的遗传学、细胞、分子和体内生物学相结合，在多学科的努力下发现用于细胞和体内系统的概念验证（POC）分子探针。探针有助于改变生物医学的进步，对公众健康和生活质量产生影响。Scripps中心在MLSCN试点阶段的生产能力通过在PUBCHEM上发表bbbb68项试验来证明，优化了5个分子靶点的POC探针，并发表了具有低纳摩尔效力、选择性和体内功效的探针，以确定新的生物和治疗靶点。该中心维持了全面的生产能力，用于分析开发和1536口井的uHTS实施（bbb20 /年）。bbb80个数据集以2个完整文库分析/月的速度在PUBCHEM上发表。仅在过去的12个月里，就发表了27项uHTS活动（包括20项基于原细胞的筛选），针对8个不同靶点类别的18个分子靶点，使用8种检测格式（来自13个外部pi）。内部发现项目在一个bb60万的化合物库上进行筛选，超过了MLPCN的要求。这些数据是在井体积（5-10 ul）内以低成本获得的。该中心节省NIH化合物收集和控制成本，每年使用2 ul化合物溶液用于24个主要筛选，只需5 ul用于hit-picks，重新确认和10点滴定。格式包括离子通量和GPCR分析，报告基因，转录因子和核受体分析，酶分析，蛋白质-蛋白质和蛋白质- rna相互作用和表型筛选。目前，该中心每年通过再合成、化学信息学、药物化学、二级和特异性分析实施以及筛选药代动力学/代谢研究来支持8个项目的靶向探针化学合成。该中心开发了跨基因家族和酶的高通量选择性分析新技术，用于优化目标选择性探针。该综合中心通过满足3个目标（目标1：每年开发25项检测以达到HTS准备水平）来支持大多数目标类别的POC探针的生产发现。2：每年对300-500,000个化合物进行25次uHTS筛选，并向PUBCHEM发布有质量保证的数据。3：优化细胞和/或体内探针或POC的筛选命中数，每年10-15个项目。该中心提供公共数据、工具和资源，以提高NIH路线图的成功和对人类健康的影响。