High Throughput Assays to Identify Inhibitors of SUMO-mediated Protein-Protein In

高通量测定法鉴定 SUMO 介导的蛋白质-蛋白质抑制剂

基本信息

批准号：
8413730
负责人：
Yuan Chen
金额：
$ 4.15万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
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：
2009-06-05 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8413730
关键词：
Address Animal Cancer Model Animal Model Binding Biochemical Biological Assay Biomedical Research Cell Cycle Progression Cell Density Cell Line Cell model Cells DNA Damage DNA Repair DNA Repair Pathway Data Dimethyl Sulfoxide Disease Docking Dose FDA approved Fluorescence Resonance Energy Transfer Future Genetic Transcription Goals Image Laboratories Lead Libraries Life Ligands Malignant Neoplasms Mediating Modification Molecular Molecular Bank Molecular Target Noise Nuclear Pathway interactions Peptides Pharmaceutical Preparations Post-Translational Protein Processing Production Property Protein Family Proteins Radiation Reporting Role Screening procedure Signal Transduction Site Technology Testing Therapeutic Human Experimentation Ubiquitin Ubiquitination United States Food and Drug Administration Variant Virus Diseases anti-cancer therapeutic base cancer cell chemotherapy design effective therapy high throughput screening human disease inhibitor/antagonist innovation multicatalytic endopeptidase complex neoplastic cell novel protein protein interaction public health relevance response

项目摘要

DESCRIPTION (provided by applicant): One of the biggest challenges in biomedical research is to design ligands for novel molecular targets so as to better understand the molecular mechanisms of life-threatening diseases and develop innovative, more effective treatments. Regrettably, progress along this line has been slow / among the approximately 50 new drugs approved by the Food and Drug Administration each year, only 3 - 5 address a new molecular target. SUMO (Small Ubiquitin-like Modifier) is one of the newly identified targets with importance in treating cancer and viral infection, for which inhibitors have not been developed to date. Protein modifications by the SUMO family of proteins regulate essential functions such as gene transcription, cell cycle progression and DNA repair. Our preliminary data has shown that inhibition of SUMO-mediated protein-protein interactions can inhibit DNA repair and sensitize cancer cells to chemotherapy and radiation. The overall goal of the proposal is to develop high throughput screening (HTS) assays to identify inhibitors for SUMO-dependent protein-protein interactions. Inhibitors of the homologous ubiquitin-proteosome pathway have been critical in studies of ubiquitin- dependent degradation and have also been extremely successful as anti-cancer therapeutics. Inhibitors of SUMO-dependent protein-protein interactions hold similar promise and could lead to the establishment of a new paradigm in the treatment of human diseases. We propose to develop HTS assays using the AlphaScreen technology, fluorescence resonance energy transfer and cell- based high content imaging approaches to identify such inhibitors. These assays will be used in automated high throughput screening (HTS) by the Molecular Libraries Production Centers Network (MLPCN). We will also perform studies using cellular and animal models to determine the research and therapeutic potentials of the lead inhibitors identified from HTS. PUBLIC HEALTH RELEVANCE: The overall goal of this proposal is to develop high throughput screening assays (HTS) to identify inhibitors for SUMO-mediated protein-protein interactions.

描述（由申请人提供）：生物医学研究中最大的挑战之一是为新的分子靶标设计配体，以便更好地了解危及生命的疾病的分子机制并开发创新、更有效的治疗方法。遗憾的是，这方面的进展一直很缓慢/美国食品和药物管理局每年批准的大约 50 种新药中，只有 3 - 5 种针对新的分子靶点。 SUMO（小泛素样修饰剂）是新发现的对治疗癌症和病毒感染具有重要意义的靶点之一，迄今为止尚未开发出针对这些疾病的抑制剂。 SUMO 蛋白家族的蛋白修饰可调节基因转录、细胞周期进程和 DNA 修复等基本功能。我们的初步数据表明，抑制 SUMO 介导的蛋白质-蛋白质相互作用可以抑制 DNA 修复并使癌细胞对化疗和放疗敏感。该提案的总体目标是开发高通量筛选 (HTS) 测定法，以鉴定 SUMO 依赖性蛋白质-蛋白质相互作用的抑制剂。同源泛素-蛋白酶体途径的抑制剂在泛素依赖性降解的研究中至关重要，并且作为抗癌疗法也非常成功。 SUMO 依赖性蛋白质-蛋白质相互作用的抑制剂具有类似的前景，并可能导致建立人类疾病治疗的新范例。我们建议使用 AlphaScreen 技术、荧光共振能量转移和基于细胞的高内涵成像方法开发 HTS 测定法来识别此类抑制剂。这些测定将由分子图书馆生产中心网络 (MLPCN) 用于自动化高通量筛选 (HTS)。我们还将使用细胞和动物模型进行研究，以确定从 HTS 中鉴定出的先导抑制剂的研究和治疗潜力。公共健康相关性：该提案的总体目标是开发高通量筛选测定法 (HTS)，以识别 SUMO 介导的蛋白质-蛋白质相互作用的抑制剂。