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: 7945401
• 负责人: HUGH ROSEN
• 金额: $ 1540.45万
• 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/7945401
• 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，通过多学科努力发现细胞和体内系统的概念验证 (POC) 分子探针。探针有助于转变生物医学进步，从而影响公共健康和生活质量。斯克里普斯中心在 MLSCN 试点阶段的生产能力 通过在 PUBCHEM 中发布超过 68 种检测方法、优化 5 个分子靶点的 POC 探针以及经过同行评审的具有低纳摩尔效力、选择性和体内功效的探针的出版物来证明，以确定新的生物和治疗靶点。该中心拥有用于检测开发和 1536 孔格式（>20/年）的 uHTS 实施的完整生产能力。 >80 个数据集 以每月 2 次完整文库分析的速度发表在 PUBCHEM 上。仅在过去 12 个月内，就发布了 27 个 uHTS 活动，包括 20 个基于细胞的初级筛选，针对 8 个不同目标类别的 18 个分子目标，使用 8 种检测格式（来自 13 个外部 PI）。内部发现项目在超过 600,000 个化合物库中进行筛选，超出了 MLPCN 的要求。这些数据以低成本的孔体积（5-10 ul）获得。该中心节省了 NIH 化合物收集并控制成本，每年使用 2 ul 化合物（溶液进行 24 次初步筛选，仅需要 5 ul 进行命中选择、重新确认和 10 点滴定。格式包括离子流和 GPCR 测定、报告基因、转录因子和核受体测定、酶测定、蛋白质-蛋白质和 蛋白质-RNA 相互作用和表型筛选。该中心目前支持每年 8 个项目的从命中到探针的化学合成，包括再合成、化学信息学、药物化学、二级和特异性测定实施以及筛选药代动力学/代谢研究，以实现有效的探针优化。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，以优化目标选择性探针。 该综合中心通过满足 3 个目标，支持大多数目标类别的 POC 探针的生产发现（目标 1：每年开发 25 项检测，以做好 HTS 准备。2：每年对 300-500,000 种化合物实施 25 次 uHTS 筛选，并向 PUBCHEM 发布有质量保证的数据。3：每年优化细胞和/或体内探针或 POC 的筛选命中，持续 10-15 个项目。该中心向公众提供数据、工具和资源可以增强 NIH 路线图的成功及其对人类健康的影响。