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.

描述（由适用提供）：激素疗法已导致雌激素受体（ER）阳性乳腺癌的妇女的存活情况得到了极大的改善。然而，残留的肿瘤细胞通常会抗抗雌激素治疗，导致回报通常比原始癌症更具侵略性。当前的ER靶向激素疗法包括选择性雌激素受体调节剂（例如他莫昔芬，雷昔芬），纯拮抗剂（例如Fulvestort）和芳香酶抑制剂，所有这些都会导致延长/慢性使用后的耐药性。此外，服用Serm的女性还经历了子宫内膜增厚/增生，息肉和癌症的发生率增加。已经描述了多种机制，产生了这些有害影响。然而，最近证明，跨越G蛋白偶联受体GPER的7跨膜已被证明有助于子宫中的马耐药性和脱靶作用。这一结论得到了以下事实的支持：抗雌激素是GPER的激动剂，而GPER激活了生长因子受体途径在激素耐药中很重要。在我们以前的工作中，我们发现并表征了不结合ERα或ERβ的GPER的新型选择性配体。但是，迄今为止，尚无已知的配体具有反相反的选择性。为了实现这一总体目标，我们已经确定了一个新型的小分子家族，这些家族对ERα和ERβ与GPER具有很高的选择性。由于雌激素和电流抗雌激素无法区分ERα/β和GPER，我们新鉴定的小分子为创建新型配体和治疗剂提供了有选择性操纵和靶向经典ER的机会。我们的假设是，通过对第一代ERα/β选择性化合物进行选定的化学修饰，我们将优化总体亲和力，接收器选择性和激动剂/拮抗剂谱，其最终目标是创建真正的ERα选择性拮抗剂。该建议的具体目的是1。根据我们的高度ERα/β选择性支架设计和合成一组衍生物； 2。在体外评估和优先考虑这些化合物的受体结合，细胞活化/抑制快速和基因组途径的抑制，细胞增殖和毒性和3。 PDX肿瘤。这些目标的成功完成应使得对ERα，ERβ和GPER的配体选择性的了解，并确定创新化合物的鉴定，这些化合物为雌激素生物学和生理学的研究提供了新型的药物工具，并且随着其在临床中的成功应用，并在临床上的成功率降低了抗乳腺癌的发展，并最终增强了抗乳腺癌的效果。乳腺癌女性的生活。