Development of GPR30-Selective Ligands

GPR30选择性配体的开发

基本信息

批准号：
7837750
负责人：
JEFFREY B ARTERBURN
金额：
$ 31.01万
依托单位：
UNIVERSITY OF NEW MEXICO
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：
2008-08-05 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7837750
关键词：
Adhesions Affect Agonist American Cancer Society Amino Acids Animal Care and Use Committees Animals Antiviral Agents Apoptosis Area Arizona Aromatic Compounds Award Back Basic Science Binding Biochemistry Bioinformatics Biological Biological Assay Biological Models Biological Process Biology Biomedical Research Biotechnology Blood Vessels Breast Breast Cancer Treatment Breast Carcinoma Cancer Biology Cancer Center Cancer Patient Cancer Research Project Carbohydrates Cell Adhesion Cell Nucleus Cellular Assay Cervix Uteri Cessation of life Chemicals Chemistry Collection Complement Complex Cytometry Data Development Disease Doctor of Philosophy Drug Delivery Systems Drug Industry Endometrial Carcinoma Endometrium Epidermal Growth Factor Receptor Estradiol Estrogen Antagonists Estrogen Nuclear Receptor Estrogen Receptor 2 Estrogen Receptors Estrogens Female Flow Cytometry Foundations Funding G Protein-Coupled Receptor Genes GTP-Binding Proteins Goals Grant Growth Growth and Development function Homeostasis Hormones Human body Immune system Incidence Institutes Label Laboratories Lead Leadership Legal patent Leukocytes Libraries Ligand Binding Ligands Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Mediating Mediator of activation protein Membrane Molecular Molecular Bank Molecular and Cellular Biology National Institute of Allergy and Infectious Disease National Institute of Environmental Health Sciences National Institute of General Medical Sciences Nature New Mexico Nucleosides Ovary Pathology Pharmaceutical Chemistry Phosphatidylinositols Phosphorylation Physiological Physiology Play Postdoctoral Fellow Publications Publishing Quantitative Structure-Activity Relationship Radioisotopes Recruitment Activity Regulation Reproduction Reproductive Biology Research Research Proposals Resource Sharing Resources Role Science Screening Result Screening procedure Selective Estrogen Receptor Modulators Signal Pathway Signal Transduction Societies Structure Structure-Activity Relationship Study Section Sweden Synthesis Chemistry TNFRSF5 gene Tamoxifen Technology Therapeutic Therapeutic Agents Therapeutic Intervention Time Tissues Transcriptional Activation United States United States National Institutes of Health Universities Washington Woman Work anticancer research base cell motility chemical property cheminformatics computer studies design drug discovery experience feeding female reproductive system improved in vivo malignant breast neoplasm member model development molecular assembly/self assembly mouse model neoplastic new technology novel overexpression professor programs public health relevance receptor release of sequestered calcium ion into cytoplasm reproductive research and development response skeletal small molecule tool trafficking treatment center virtual

项目摘要

DESCRIPTION (provided by applicant): Estrogen is a critical hormone in the human body that regulates the growth, development and homeostasis of many tissues. Physiological responses to estrogen include the regulation of mammalian reproduction and breast function, central nervous and immune systems, skeletal physiology and vascular function. We have recently described novel functions of the seven transmembrane G protein-coupled estrogen receptor, GPR30. This receptor is activated by both agonists and antagonists of the classical estrogen receptors, ER1 and ER2. Until recently there were no known specific ligands for GPR30, making traditional pharmacological approaches to the study of this receptor difficult. Our recent studies however have combined both virtual and biomolecular screening to discover the first GPR30-selective agonist, G-1. The specific aims of this application are: 1. Perform a combination of virtual and biomolecular screening to identify additional GPR30-specific ligands based on compounds presently known to bind and activate GPR30. Structure-activity analyses will be carried out to determine the critical molecular determinants for GPR30 binding selectivity and activity as compared to classical estrogen receptors. 2. Based on the biomolecular screening results and structure-activity analyses of Aim 1, rationally design and synthesize small libraries (up to 20 compounds per cycle) of novel G-1-based ligands. The goal of this aim is to separate agonism from antagonism within ligands, and to further evaluate the SAR of novel GPR30 ligands through targeted synthetic chemistry. 3. Characterize the biological functions of the compounds identified and synthesized in Aims 1 and 2. A collection of functional bioassays will be employed to characterize the biological effects of the compounds displaying activity. These assays will include intracellular signaling assays such as calcium mobilization, ERK and EGFR phosphorylation and PI3K activation; more complex cellular assays such as transcriptional activation, cell migration and proliferation; and in vivo studies using mouse models. Understanding the pharmacological profile and structure-activity relationships for ligand binding to GPR30 will be critical to the discovery of novel drugs that target this receptor for the purposes of revealing the underlying physiology of the receptor and developing therapeutic approaches for the improved treatment of estrogen-dependent cancers. PUBLIC HEALTH RELEVANCE: Estrogen plays an important role in normal and disease biology. We have characterized a novel membrane estrogen receptor that likely plays a role in estrogen biology. The goal of this work is to develop novel compounds that can specifically target this new receptor to either activate or inhibit its activity without affecting other estrogen receptors.

描述（由申请人提供）：雌激素是人体中的一种关键激素，可调节许多组织的生长，发育和稳态。对雌激素的生理反应包括调节哺乳动物繁殖和乳房功能，中枢神经和免疫系统，骨骼生理学和血管功能。我们最近描述了七个跨膜G蛋白偶联雌激素受体GPR30的新功能。该受体被经典雌激素受体ER1和ER2的激动剂和拮抗剂激活。直到最近，GPR30还没有已知的特异性配体，使该受体的研究变得传统。然而，我们最近的研究将虚拟和生物分子筛选结合在一起，发现了第一个GPR30选择性激动剂G-1。该应用程序的具体目的是：1。执行虚拟和生物分子筛选的组合，以基于目前已知可以结合和激活GPR30的化合物来识别其他GPR30特异性配体。与经典的雌激素受体相比，将进行结构活性分析，以确定GPR30结合选择性和活性的关键分子决定因素。 2。基于AIM 1的生物分子筛选结果和结构活性分析，合理设计并合成了新型基于G-1的配体的小型文库（每个周期最多20种化合物）。该目标的目的是将激动剂与配体内的拮抗作用分开，并通过靶向的合成化学进一步评估新型GPR30配体的SAR。 3。表征目标1和2中鉴定和合成的化合物的生物学功能。将采用功能性生物测定的集合来表征显示活性的化合物的生物学作用。这些测定将包括细胞内信号传导测定法，例如钙动员，ERK和EGFR磷酸化和PI3K激活。更复杂的细胞分析，例如转录激活，细胞迁移和增殖；并使用小鼠模型进行体内研究。了解配体与GPR30结合的药理特征和结构活性关系对于发现该受体的新药物至关重要，以揭示受体的潜在生理学和开发治疗方法，以改善雌激素依赖性癌症的治疗方法。公共卫生相关性：雌激素在正常和疾病生物学中起重要作用。我们表征了一种新型的膜雌激素受体，该受体可能在雌激素生物学中起作用。这项工作的目的是开发新的化合物，这些化合物可以专门针对该新受体以激活或抑制其活性而不会影响其他雌激素受体。