Kinome Drug Bioassay Platform

Kinome药物生物测定平台

• 批准号: 6935506
• 负责人: HAICHING MA
• 金额: $ 10万
• 依托单位: REACTION BIOLOGY CORPORATION
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6935506
• 关键词: bioassay; biological signal transduction; biotechnology; combinatorial chemistry; drug discovery /isolation; genetic screening; high throughput technology; microarray technology; peptide library; phosphoprotein phosphatase; protein protein interaction; protein tyrosine kinase; serine threonine protein kinase; technology /technique development

DESCRIPTION (provided by applicant): Protein kinases play pivotal roles in signal transactions, and dysfunction of them is a key factor for diseases like cancer, inflammation, diabetes etc. Kinome drug discovery is a major focus in pharmaceutical industry, and high throughput screening (HTS) is a major tool for lead discovery. Reaction Biology Corporation's (RBC) Discovery Dot miniaturization technology will not only facilitate the drug discovery process but also save the cost by millions. RBC has developed extremely versatile nanoliter reaction microarrays to serve markets for ultra uHTS drug discovery, large scale IC50 determinations, and large scale IC50 selectivity/toxicity profiling. These reactions are 1000 to 10,000-fold smaller than well plate formats currently used widely in drug discovery. Through the power of contact printing, RBC has the capacity to print and activate over 3 million reactions per week. Currently, 3072 drug screening reactions can be carried out on a single microarray. The ability to print large chemical libraries in hundreds of replicates sets for kinase and phosphatase screening can drive chemical-proteomic research, environmental toxicology, hit discovery and prioritization, lead selection, and ADMET. In preliminary studies, RBC has demonstrated the ability to conduct calibrated screening of human protein kinases (c-src, PKA) using printed microarrays. Through Phase I funding, the proposed research will focus on the following three aims: Aim 1 Validation of 5 tyrosine kinase and 5 serine/threonine kinase assays with Z'>0.6 and further optimization to achieve the lowest cost assays in the industry; Aim 2 Design, implementation, and validation of new assay methods for kinases and phosphatases that are amenable to microarray-based screening of chemical libraries; Aim 3 Validation of kinase and phosphatase HTS on microarrays against well-plate assay using a standardized screening library. This work will enable Phase II activities where Reaction Biology will expand its assay range across the human kinome using a universal kinase assay against large synthetic and natural libraries.

产品描述（申请人提供）：蛋白激酶在信号传递中起着关键作用，其功能障碍是癌症、炎症、糖尿病等疾病的关键因素。激酶组药物发现是制药行业的主要焦点，高通量筛选（HTS）是先导化合物发现的主要工具。Reaction Biology Corporation（RBC）的Discovery Dot微型化技术不仅可以促进药物发现过程，还可以节省数百万美元的成本。RBC已经开发出非常通用的纳升反应微阵列，以服务于超uHTS药物发现、大规模IC 50测定和大规模IC 50选择性/毒性分析的市场。这些反应比目前广泛用于药物发现的孔板形式小1000至10，000倍。通过接触式打印的力量，RBC有能力每周打印和激活超过300万个反应。目前，3072个药物筛选反应可以在单个微阵列上进行。在用于激酶和磷酸酶筛选的数百个重复集中打印大型化学文库的能力可以推动化学蛋白质组学研究、环境毒理学、命中发现和优先级排序、先导选择和ADMET。在初步研究中，RBC已经证明了使用打印的微阵列对人类蛋白激酶（c-src，PKA）进行校准筛选的能力。通过第一阶段的资助，拟议的研究将集中在以下三个目标：目标1验证5个酪氨酸激酶和5个丝氨酸/苏氨酸激酶测定法，Z '> 0.6，并进一步优化，以实现行业中最低成本的测定法;目标2设计，实施和验证新的激酶和磷酸酶测定方法，这些方法适用于基于微阵列的化学文库筛选;目的3利用标准化筛选文库验证激酶和磷酸酶基因芯片的HTS。这项工作将实现第二阶段活动，其中Reaction Biology将使用针对大型合成和天然库的通用激酶测定来扩大其在人类激酶组中的测定范围。