Development of GPR30-Selective Ligands

GPR30选择性配体的开发

基本信息

批准号：
8245232
负责人：
JEFFREY B ARTERBURN
金额：
$ 5.26万
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/8245232
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 Cell Proliferation Cellular Assay Cervix Uteri Cessation of life Chemicals Chemistry Collection Complement Complex Coupled 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 Receptors Estrogens Female Flow Cytometry Foundations Funding G Protein-Coupled Receptor Genes GTP-Binding Proteins Goals Grant Growth Growth and Development function Health 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 NCI Center for Cancer Research National Center for Research Resources National Institute of Allergy and Infectious Disease National Institute of Environmental Health Sciences National Institute of General Medical Sciences Nature Neuraxis 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 cancer therapy 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 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）：雌激素是人体内的一种重要激素，调节许多组织的生长、发育和体内平衡。对雌激素的生理反应包括哺乳动物生殖和乳腺功能、中枢神经和免疫系统、骨骼生理和血管功能的调节。我们最近描述了七跨膜 G 蛋白偶联雌激素受体 GPR30 的新功能。该受体可被经典雌激素受体 ER1 和 ER2 的激动剂和拮抗剂激活。直到最近，还没有已知的 GPR30 特异性配体，这使得传统药理学方法研究该受体变得困难。然而，我们最近的研究结合了虚拟和生物分子筛选，发现了第一个 GPR30 选择性激动剂 G-1。该应用的具体目标是： 1. 结合虚拟和生物分子筛选，根据目前已知的结合和激活 GPR30 的化合物来鉴定其他 GPR30 特异性配体。将进行结构-活性分析，以确定与经典雌激素受体相比，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构效分析，合理设计并合成基于G-1的新型配体小库（每个循环最多20个化合物）。该目的的目的是将配体内的激动作用与拮抗作用分开，并通过靶向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功能。将采用一系列功能生物测定来表征表现出活性的化合物的生物效应。这些检测将包括细胞内信号转导检测，例如钙动员、ERK 和 EGFR 磷酸化以及 PI3K 激活；更复杂的细胞测定，例如转录激活、细胞迁移和增殖；以及使用小鼠模型的体内研究。了解配体与 GPR30 结合的药理学特征和构效关系对于发现针对该受体的新药至关重要，从而揭示受体的潜在生理学并开发治疗方法以改善雌激素依赖性的治疗癌症。公共卫生相关性：雌激素在正常和疾病生物学中发挥着重要作用。我们已经表征了一种可能在雌激素生物学中发挥作用的新型膜雌激素受体。这项工作的目标是开发新的化合物，可以特异性靶向这种新受体，激活或抑制其活性，而不影响其他雌激素受体。