Rapid Kinase Profiling with Luminescent Reporters

使用发光报告基因快速分析激酶

基本信息

批准号：
7745380
负责人：
REENA ZUTSHI
金额：
$ 13.59万
依托单位：
LUCEOME BIOTECHNOLOGIES, LLC
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7745380
关键词：
Active Sites Arizona Binding Binding Proteins Biological Assay Bioluminescence Boxing Catalytic Domain Cells Chemicals Clinical Trials Code Collection Cyclic AMP-Dependent Protein Kinases Data Development Diabetes Mellitus Dimerization Disease Drug Industry Environment Enzymes Fluorescence Fluorescence Polarization Fluorescence Resonance Energy Transfer Freedom Gefitinib Gene Family Generations Genes Genome Gleevec Goals Hour Human Human Biology Human Genome Image Imatinib In Vitro Intervention Label Lead Legal patent Libraries Licensing Ligands Light Literature Luciferases Malignant Neoplasms Maps Marketing Measurement Mediation Methodology Methods Modeling Monitor Mutation PKC412 Peptides Pharmaceutical Preparations Phase Phosphotransferases Physiological Production Protein Kinase Proteins Radioactive Regulation Reporter Role Safety Screening procedure Services Signal Pathway Signal Transduction Signal Transduction Pathway Small Business Innovation Research Grant Source Specificity Staurosporine Sutent System Techniques Technology Therapeutic Agents Universities Washington base commercialization drug discovery flavopiridol high throughput screening hydroxyl group in vitro Assay inhibitor/antagonist interest kinase inhibitor luciferin luminescence novel protein expression public health relevance scaffold small molecule tool

项目摘要

DESCRIPTION (provided by applicant): More than 500 different protein kinases have been identified in humans and represent 1.7% of the human genome. Protein kinases function by catalyzing the transfer of the 3-phosphoryl group of ATP to the hydroxyl group on a specific protein substrate. The central role of kinases in disease and their fundamental role in human biology have prompted the development of potent and selective inhibitors as therapeutic agents and as novel tools for dissecting kinase function in the context of signal transduction pathways. Because many human kinases are so closely related both genetically and structurally, many inhibitors lack specificity for a single target and act on more than one kinase, typically by out-competing ATP in the active site. Hence there is a need for comprehensive kinase panels and tools for selectivity assessment of drugs. The kinase screening and profiling market was estimated to be $106 MM in 2008 and the demand is steadily rising every year. The purpose of our application is to develop a luminescence-based, homogeneous, non- radioactive, sensitive, cell-free assay that can be rapidly adapted for high throughput (HTP) screening and profiling of small molecule antagonists of kinases. The utility of this assay against commercially available drugs/dug candidates and the selectivity of these molecules against a kinase panel will be demonstrated. PUBLIC HEALTH RELEVANCE: Kinases constitute 1.7% of the genome and are implicated in various diseases, from cancer to diabetes. Assessment of selectivity of drugs against kinases is critical to evaluate their physiological safety. The purpose of our application is to develop a method to identify selective drugs by profiling them against a kinase panel.

描述（由申请人提供）：已在人类中鉴定出500多种不同的蛋白激酶，占人类基因组的1.7％。蛋白激酶通过催化特异性蛋白质底物上的3-磷酸基ATP向羟基的转移来发挥作用。激酶在疾病中的核心作用及其在人类生物学中的基本作用促使有效和选择性抑制剂作为治疗剂的发展和作为在信号传输途径中剖析激酶功能的新工具。由于许多人类激酶在遗传和结构上都是如此紧密相关，因此许多抑制剂对单个靶标缺乏特异性，并且对多种激酶作用，通常是通过在活性位点中能努力的ATP。因此，需要全面的激酶面板和工具来评估药物。激酶筛查和分析市场在2008年为106毫米，需求每年稳步上升。我们应用的目的是开发基于发光的，均匀的，非放射性，灵敏的，无细胞的测定法，可以快速适应高吞吐量（HTP）筛选和对激酶小分子拮抗剂的分析。将证明该测定法对市售药物/DUG候选物的实用性以及这些分子对激酶面板的选择性。公共卫生相关性：激酶占基因组的1.7％，与从癌症到糖尿病的各种疾病有关。评估药物对激酶的选择性对于评估其生理安全至关重要。我们应用的目的是开发一种方法来通过对激酶面板进行分析来识别选择性药物。