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(申请人提供)：荷尔蒙疗法已导致雌激素受体(ER)阳性乳腺癌患者的存活率得到极大改善。然而，残留的肿瘤细胞往往对抗雌激素治疗产生抗药性，导致复发，通常比原始癌症更具侵袭性。目前针对雌激素受体的激素治疗包括选择性雌激素受体调节剂(如他莫昔芬、雷洛昔芬)、纯拮抗剂(如福维斯特)和芳香化酶抑制剂，所有这些药物在长期/长期使用后都可能导致耐药性。此外，服用SERM的妇女还会增加子宫内膜增厚/增生、息肉和癌症的发生率。产生这些有害影响的机制有多种；然而，最近的研究表明，跨越G蛋白偶联受体GPER的7-跨膜在子宫中既能引起激素抵抗，又能引起非靶点效应。这一结论得到以下事实的支持：抗雌激素作为GPER的激动剂，GPER激活在荷尔蒙抵抗中重要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与ERα或ERβ结合的新型选择性GPER配体。然而，到目前为止，还没有已知的配体表现出相反的选择性。为了实现这一总体目标，我们已经确定了一系列对ERα和ERβ具有高度选择性的新型小分子。由于雌激素和现有的抗雌激素药物不能区分ER、α/β和GPER，我们新发现的小分子为创造新的配体和治疗剂提供了机会，以选择性地操纵和靶向经典的ER。我们的假设是，通过对这种第一代ERα/β选择性化合物的选择性化学修饰，我们将优化整体亲和力、受体选择性和激动剂/拮抗剂图谱，最终目标是创造一个真正的ERα选择性拮抗剂。这项建议的具体目标是1.设计和合成一套基于我们高度选择性ERα/β支架的衍生物；2.在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、细胞增殖和毒性以及3.确定化合物在体内调节雌激素依赖的生理的能力，特别是先导化合物在荷ER依赖和抗雌激素抵抗的异种移植瘤、原位移植瘤和PDX肿瘤中的抗肿瘤特性。这些目标的成功实现将有助于更好地了解ERα、ERβ和GPER的配体选择性，鉴定为雌激素生物学和(病理)生理学研究提供新型药理学工具的创新化合物，并随着它们在临床上的成功应用，减少乳腺癌抗雌激素耐药复发和子宫内膜的非靶点效应，最终提高乳腺癌女性患者的生存和生活质量。