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

• 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
• 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

 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）：激素治疗已导致雌激素受体（ER）阳性乳腺癌妇女的生存率大大提高。然而，残留的肿瘤细胞通常对抗雌激素治疗产生抗性，导致复发，其通常比原始癌症更具侵袭性。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，所有这些都可以在长期/慢性使用后导致抗性。此外，服用SERM的女性也会增加子宫内膜增厚/增生、息肉和癌症的发病率。已经描述了产生这些有害作用的多种机制;然而，最近已证明7跨膜G蛋白偶联受体GPER有助于子宫中的激素抵抗和脱靶效应。这一结论得到了以下事实的支持：抗雌激素类药物可作为GPER的激动剂，并且GPER可激活在激素抵抗中起重要作用的生长因子受体途径。在我们以前的工作中，我们已经发现并表征了不结合ERα或ERβ的GPER的新型选择性配体。然而，迄今为止，还没有已知的配体表现出逆选择性。 为了实现这一总体目标，我们已经确定了一个新的小分子家族，其对ERα和ERβ相对于GPER具有高度选择性。由于雌激素和目前的抗雌激素不能区分ERα/β和GPER，我们新鉴定的小分子提供了创造新的配体和治疗剂以选择性地操纵和靶向经典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择性化学修饰，我们将优化总体亲和力、受体选择性和激动剂/拮抗剂特征，最终目标是创造一种真正的ERα选择性拮抗剂。该提案的具体目标是1。设计并合成一系列基于ERα/β高选择性支架的衍生物; 2.在体外评价这些化合物的受体结合、细胞活化/快速和基因组途径的抑制、细胞增殖和毒性，并对其进行优先排序;确定化合物在体内调节雌激素依赖性生理学的能力，特别是先导化合物在携带ER依赖性和抗雌激素抗性异种移植物、原位和PDX肿瘤的小鼠中的抗肿瘤特性。 这些目标的成功实现将导致更好地理解ERα、ERβ和GPER的配体选择性，鉴定为雌激素生物学和（病理）生理学研究提供新药理学工具的创新化合物，以及随着其在临床中的成功应用，减少乳腺癌抗雌激素抗性复发的发展和子宫内膜中的脱靶效应，最终提高乳腺癌患者的生存率和生活质量。