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Molecular Mechanisms and Applications of Novel ER/GPER-selective Ligands

新型ER/GPER选择性配体的分子机制及应用

基本信息

批准号：
9027453
负责人：
JEFFREY B ARTERBURN
金额：
$ 32万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-07 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9027453
关键词：
Adverse effects Affinity Agonist Aromatase Inhibitors Binding Biological Biological Assay Biology Breast Cancer Cell Cell Line Cell Proliferation Cell Survival Cells Chemicals Chronic Clinic Development Disease Disseminated Malignant Neoplasm Drug Targeting Endometrial Endometrial Carcinoma Endometrium Estrogen Antagonists Estrogen Nuclear Receptor Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogen receptor positive Estrogens Evaluation Exhibits Family Fulvestrant G-Protein-Coupled Receptors GPER gene Generations Genomics Goals Growth Growth Factor Receptors Health Hormonal Hyperplasia In Vitro Incidence Individual Lead Letrozole Ligands Malignant Neoplasms Malignant neoplasm of lung Mammary Neoplasms Mediating Modeling Modification Molecular Mus Names Nature Neoplasm Metastasis Outcome Ovarian Pathway interactions Patients Performance Pharmaceutical Preparations Physiological Physiology Polyps Prevention Production Property Quality of life RBM5 gene Raloxifene Recurrence Recurrent Malignant Neoplasm Reporter Reporting Research Research Personnel Residual Tumors Resistance Resistance development Risk Selective Estrogen Receptor Modulators Series Signal Transduction Staging Structure Tamoxifen Therapeutic Agents Thromboembolism Toxic effect Transcriptional Regulation Translations Uterine Neoplasms Uterus Woman Work Xenograft procedure analog antitumor agent base cross reactivity design experience fight against hormone resistance hormone therapy in vivo innovation malignant breast neoplasm neoplastic cell next generation sequencing novel novel strategies novel therapeutics receptor receptor binding scaffold small molecule targeted treatment tool transcriptome sequencing tumor tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Hormonal therapies have led to great improvements in the survival of women with estrogen receptor (ER)-positive breast cancers. However, residual tumor cells often become resistant to anti-estrogen treatment resulting in recurrences that are frequently more aggressive than the original cancer. Current ER- targeted hormonal therapies include selective estrogen receptor modulators (e.g. tamoxifen, raloxifene), pure antagonists (e.g. fulvestrant) and aromatase inhibitors, all of which can result in resistance following prolonged/chronic use. In addition, women taking SERMs also experience an increased incidence of endometrial thickening/hyperplasia, polyps and cancer. Multiple mechanisms have been described yielding these deleterious effects; however, most recently the 7-transmembrane spanning G protein-coupled receptor GPER has been demonstrated to contribute to both hormonal resistance and off-target effects in the uterus. This conclusion is supported by the fact that anti-estrogens act as agonists for GPER and that GPER activates growth factor receptor pathways that are important in hormonal resistance. In our previous work, we have discovered and characterized novel selective ligands for GPER that do not bind ERα or ERβ. To date however, there are no known ligands that exhibit the inverse selectivity. Towards this overall goal, we have identified a family of novel small molecules that are highly selective for ERα and ERβ vs. GPER. As estrogen and current anti-estrogens cannot distinguish between ERα/β and GPER, our newly identified small molecule provides the opportunity to create novel ligands and therapeutic agents to selectively manipulate and target classical ERs. Our hypothesis is that through selected chemical modifications to this first generation ERα/β-selective compound, we will optimize the overall affinity, receptor selectivity and agonist/antagonist profile with the ultimate goal of creating a truly ERα-selective antagonist. The specific aims of this proposal are 1. To design and synthesize a suite of derivatives based on our highly ERα/β-selective scaffold; 2. To evaluate and prioritize these compounds in vitro for receptor binding, cellular activation/inhibition of rapid and genomic pathways, cell proliferation and toxicity and 3. To determine the ability of compounds to modulate estrogen-dependent physiology in vivo, particularly the anti- tumor properties of lead compounds in mice bearing ER-dependent and anti-estrogen-resistant xenograft, orthotopic and PDX tumors. The successful completion of these aims should result in a better understanding of the ligand selectivity of ERα, ERβ and GPER, the identification of innovative compounds that provide novel pharmacological tools for the study of estrogen biology and (patho)physiology, and, with their successful application in the clinic, reductions of the development of anti-estrogen resistant recurrences of breast cancer and off-target effects in the endometrium, ultimately enhancing survival and the quality of life of women with breast cancer.