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传导途径中发挥核心作用，并且是细胞功能的关键效应器。由于酶水平的变化或激酶结构的突变而导致的蛋白激酶活性异常是导致病理的原因。因此，蛋白激酶抑制剂有可能被开发为许多疾病的治疗方法，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与 ATP 结合直接竞争的小分子配体。然而，通过在高度保守的 ATP 位点结合来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能提供识别选择性抑制剂的方法。问题在于，检测蛋白激酶失活构象的方法并不多，而且没有一种方法可以轻松用于药物发现。 Encode Bio 开发了一种光学技术，可用于识别蛋白激酶的变构调节剂，从而稳定蛋白激酶的非活性构象。我们建议通过生成一个系统来大规模生产大型化学库高通量筛选所需的 assa 试剂，从而在开发药物发现方法方面实现下一个关键技术飞跃。公共卫生相关性：蛋白激酶在调节大多数细胞功能中发挥着重要作用。我们将开发具有通用性的新型高通量检测方法，以识别在 ATP 结合位点外结合的蛋白激酶抑制剂。这些测定可用于加速许多疾病的治疗方法的开发，包括癌症、中枢神经系统疾病和炎症。我们将加速开发具有潜在更好选择性和安全性的变构激酶抑制剂。