High Throughput Screening Technology for Allosteric Kinase Inhibitors

变构激酶抑制剂高通量筛选技术

基本信息

批准号：
7608761
负责人：
Mark W Nowak
金额：
$ 20.45万
依托单位：
ENCODE BIO, INC.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-15 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7608761
关键词：
Active Sites Affect Ala-Trp-Arg-His-Pro-Gln-Phe-Gly-Gly Amino Acids Azides BODIPY Binding Binding Sites Biological Assay Cell Line Cell physiology Cells Central Nervous System Diseases Chemistry Class Code Condition Data Development Diabetes Mellitus Disease Drug Delivery Systems Drug Industry Enzymes Fluorescence Future Generations Geneticin Gleevec Grant Growth Immunoblotting Inflammation Inflammatory Label Lead Ligands Malignant Neoplasms Measures Metabolic Diseases Molecular Conformation Monitor Movement Mutagenesis Mutation Neoplasm Metastasis Neoplasms Optics Pathology Pharmaceutical Preparations Phase Phase II Clinical Trials Phosphotransferases Plasmids Play Preclinical Drug Evaluation Preparation Production Property Protein Kinase Protein Kinase Inhibitors Proteins Public Health Reagent Reproducibility Role Safety Signal Pathway Signal Transduction Simulate Site Small Business Funding Mechanisms Small Business Innovation Research Grant Standardization Standards of Weights and Measures Structure Suspension Culture Suspension substance Suspensions System Techniques Technology Testing Therapeutic Transfer RNA Tryptophan base cell growth drug discovery fluorophore high throughput screening human disease inhibitor/antagonist kinase inhibitor miniaturize nervous system disorder novel novel strategies protein expression protein function protein kinase inhibitor scale up small molecule small molecule libraries success therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Protein kinases play a central role in many signaling pathways and are key effectors of cellular functions. Abnormalities in protein kinase activity, either due to changes in enzyme levels or mutations in the kinase structure, are responsible for pathologies. As such, protein kinases inhibitors can potentially be developed as therapeutics for many diseases, including cancer, central nervous system disorders and inflammation. Drug discovery efforts have primarily identified small molecule ligands that compete directly with ATP binding. However, molecules that inhibit one kinase by binding at the highly conserved ATP site often inhibit other kinases, resulting in potential drug safety issues. Approaches to target drugs to the inactive conformation may provide the means to identify selective inhibitors. The problem is that there are not many ways to detect the inactive conformation of protein kinases and none that can be easily employed for drug discovery. Encode Bio has developed an optical technology which can be employed to identify allosteric regulators of protein kinases that stabilize the inactive conformation of protein kinases. We propose to make the next critical technological jump in developing the approach for drug discovery by generating a system to mass produce the requisite assa reagents in quantities needed for high throughput screening of large chemical libraries. PUBLIC HEALTH RELEVANCE: Protein kinases play important roles in regulating most cellular functions. We will develop novel high throughput assays with universal utility to identify protein kinase inhibitors that bind outside the ATP-binding site. These assays could be used to accelerate the development of therapeutics for many diseases, including cancer, central nervous system disorders and inflammation. We will accelerate development of allosteric kinase inhibitors with potentially better selectivity and safety profiles.

描述（由申请人提供）：蛋白激酶在许多信号通路中起着核心作用，并且是细胞功能的关键效果。蛋白激酶活性的异常是由于酶水平的变化或激酶结构中的突变而导致的病理学。因此，蛋白激酶抑制剂可能会作为许多疾病的治疗剂，包括癌症，中枢神经系统疾病和炎症。药物发现工作主要确定了直接与ATP结合竞争的小分子配体。但是，通过在高度保守的ATP位点结合抑制一种激酶的分子通常会抑制其他激酶，从而导致潜在的药物安全问题。将药物靶向非活性构象的方法可以提供识别选择性抑制剂的手段。问题在于，没有很多方法可以检测蛋白激酶的非活性构象，而没有一种可以轻松用于药物发现的方法。编码生物已经开发了一种光学技术，该光学技术可用于鉴定蛋白激酶的变构调节剂，以稳定蛋白激酶的无活性构象。我们建议通过生成一个系统来生成一个系统的系统，以产生必要的ASSA试剂，以高吞吐量筛选大型化学文库所需的数量，从而实现下一个关键的技术跳跃。公共卫生相关性：蛋白激酶在调节大多数细胞功能方面起着重要作用。我们将开发具有通用效用的新型高通量测定，以鉴定在ATP结合位点外结合的蛋白激酶抑制剂。这些测定方法可用于加速许多疾病的治疗剂，包括癌症，中枢神经系统疾病和炎症。我们将加速具有更好的选择性和安全性谱的变构激酶抑制剂的发展。