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：
9754790
负责人：
JEFFREY B ARTERBURN
金额：
$ 31.04万
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/9754790
关键词：
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 Hormonal Hyperplasia In Vitro Incidence Individual Investigation Lead Letrozole Ligands Lung Malignant Neoplasms Mammary Neoplasms Mediating Modeling Modification Molecular Mus Names Nature Neoplasm Metastasis Outcome Ovarian Pathway interactions Patients Performance Pharmaceutical Preparations Pharmacology 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 Structure Tamoxifen Therapeutic Agents Thromboembolism Toxic effect Transcriptional Regulation Translations Uterine Neoplasms Uterus Woman Work Xenograft procedure analog antitumor agent base cross reactivity design estrogenic experience fight against hormone resistance hormone therapy in vivo innovation malignant breast neoplasm neoplastic cell next generation sequencing novel novel strategies novel therapeutics public health relevance receptor receptor binding scaffold side effect small molecule targeted treatment tool 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（由申请人提供）：激素疗法极大地改善了雌激素受体（ER）阳性乳腺癌女性的生存率，然而，残留的肿瘤细胞通常会对抗雌激素治疗产生耐药性，从而导致复发率更高。目前的 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、雷洛昔芬）、纯拮抗剂（例如氟维司群）和芳香酶抑制剂，所有这些都可能在长期/长期使用后导致耐药性。此外，服用 SERM 的女性也会出现子宫内膜增厚/增生、息肉和癌症的发生率增加，然而，大多数情况下都会产生这些有害影响。最近，跨膜 7 次的 G 蛋白偶联受体 GPER 已被证明会导致子宫内的激素抵抗和脱靶效应，这一结论得到了以下事实的支持。抗雌激素作为 GPER 的激动剂，并且 GPER 激活对激素抵抗很重要的生长因子受体途径，但迄今为止，我们已经发现并表征了不结合 ERα 或 ERβ 的新型 GPER 选择性配体。没有已知的配体表现出反向选择性，为了实现这一总体目标，我们已经确定了一系列新型小分子，它们对 ERα 和 ERβ 与雌激素和当前的 GPER 具有高度选择性。抗雌激素药物无法区分 ERα/β 和 GPER，我们新发现的小分子提供了创造新型配体和治疗剂的机会，以选择性地操纵和靶向经典 ER。我们的假设是，通过对第一代 ERα/β 进行选择性化学修饰。 -选择性化合物，我们将优化整体亲和力、受体选择性和激动剂/拮抗剂特征，最终目标是创建真正的 ERα 选择性拮抗剂。该提案的具体目标是 1. 设计和合成。一套基于我们高度 ERα/β 选择性支架的衍生物； 2. 体外评估和优先考虑这些化合物的受体结合、快速和基因组途径的细胞激活/抑制、细胞增殖和毒性； 3. 确定这些化合物的能力调节体内雌激素依赖性生理学的化合物，特别是先导化合物在具有 ER 依赖性和抗雌激素耐药性异种移植、原位和 PDX 肿瘤的小鼠中的抗肿瘤特性应该会成功完成。更好地了解 ERα、ERβ 和 GPER 的配体选择性，鉴定创新化合物，为雌激素生物学和（病理）生理学研究提供新的药理学工具，并通过其在临床的成功应用，减少乳腺癌抗雌激素耐药性复发和子宫内膜脱靶效应的发展，最终提高乳腺癌女性的生存率和生活质量。