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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：
10521965
负责人：
JEFFREY B ARTERBURN
金额：
$ 52.55万
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 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10521965
关键词：
Address Advanced Malignant Neoplasm Affinity Agonist Anabolism Aromatase Inhibitors Binding Biological Biological Assay Biology Breast Cancer Cell Cancer cell line Cell Line Cell Proliferation Cell Survival Cells Chemicals Chemoresistance Clinical Clinical Trials Development Diagnosis Disease Disseminated Malignant Neoplasm Drug Targeting Endometrial Endometrial Carcinoma Estrogen Antagonists Estrogen Receptor alpha Estrogen Receptors Estrogen receptor positive Estrogens Exhibits Fulvestrant Funding G-Protein-Coupled Receptors GPER gene Generations Genomics Goals Growth Hormonal Hyperplasia In Vitro Incidence Individual Investigation Lead Letrozole Ligands Malignant Neoplasms Mammary Neoplasms Mediating Metabolic Methods Modeling Modification Molecular Mus Names Nature Neoplasm Metastasis Nuclear Hormone Receptors Outcome Pathway interactions Patients Performance Pharmaceutical Preparations Pharmacology Phase I Clinical Trials Physiological Physiology Polyps Prevention Production Property Publishing Quality of life RBM5 gene Raloxifene Recurrence Recurrent Malignant Neoplasm Reporter Research Resistance Resistance development Risk Selective Estrogen Receptor Modulators Series Signal Transduction Steroid Receptors Steroids Structure Tamoxifen Therapeutic Agents Thromboembolism Time Toxic effect Transcriptional Regulation Transgenic Organisms Tumor-Derived Uterine Neoplasms Uterus Woman Work Xenograft procedure analog antagonist antitumor agent appendage base cancer clinical trial cross reactivity enantiomer estrogenic experience fight against hormone resistance hormone therapy improved in vivo innovation malignant breast neoplasm novel receptor receptor binding refractory cancer scaffold side effect small molecule tool transcriptome sequencing translational potential tumor tumor xenograft

项目摘要

! ! ! ! PROJECT SUMMARY Hormonal therapies have been revolutionary in the treatment of women with estrogen receptor positive (ER+) breast cancers, greatly enhancing survival. ER-targeted hormonal therapies include selective estrogen receptor modulators SERMs, such as tamoxifen, and selective estrogen receptor downregulators (SERDs), such as fulvestrant, whereas aromatase inhibitors block the biosynthesis of estrogen. These therapies have significant side effects, and their prolonged use can lead to chemoresistance in about one- third of treated women, often resulting in more aggressive cancers. Furthermore, tamoxifen use is associated with increased incidence of endometrial thickening and hyperplasia, polyps and cancer. Recent studies have identified novel pathways involving the 7-transmembrane spanning G protein-coupled receptor GPER in patients undergoing SERM/SERD therapies. Cross-reactive pharmacological agonism of GPER contributes to both hormonal resistance and off-target effects in the uterus as all clinically approved anti- estrogens act as agonists for GPER and stimulate these pathways. This critical issue of ER/GPER selectivity has not been addressed in the development of SERM and SERD drugs. In our previous work, we discovered and characterized novel selective ligands for GPER that do not bind ERa or ERb.Recently, we discovered a novel small molecule that for the very first-time targets ER without interference of GPER. As current anti-estrogens do not discriminate between ERa/b and GPER, our newly identified small molecule affords the opportunity to create novel ligands and therapeutic agents to selectively target ERa. Through chemical modifications to this first-generation ERa-selective compound, we have improved the affinity, receptor-selectivity and antagonist/agonist profile with the ultimate goal of creating truly ERa- selective antagonists. The specific aims of this proposal are to: 1. Synthesize and resolve the bioactive enantiomer of optimized ERa-targeted AB-SERD compounds with GPER anti-selectivity; 2. Prioritize compounds through in vitro methods including receptor binding, cell signaling, proliferation and toxicity and 3. Determine in vivo anti-tumor and ADMET properties of lead compounds, employing ER-dependent and anti-hormone-resistant transgenic, xenograft and PDX tumors. The successful completion of these studies will identify innovative enantiospecific compounds as unique pharmacological tools for delineating the individual functions of ER and GPER, and also initiating the development of first-in-class therapeutic agents, with the goal of reducing anti-hormone resistant recurrence of breast cancer, enhancing survival and the quality of life for the greater than 200,000 women annually diagnosed with ER-positive breast cancer. !"#$%&'()*++,"-./01'",&'( !,2%(3(

好了！好了！好了！好了！项目总结激素疗法在雌激素受体阳性妇女的治疗中具有革命性意义 (Er+)乳腺癌，大大提高了存活率。针对ER的激素疗法包括选择性雌激素受体调节剂SERM，如他莫昔芬和选择性雌激素受体下调调节剂 (SERDS)，如弗维斯特，而芳香酶抑制剂阻止雌激素的生物合成。这些治疗方法有显著的副作用，长期使用可能会导致大约1-1的化疗耐药- 三分之一的接受治疗的妇女，往往会导致更具侵袭性的癌症。此外，他莫昔芬的使用是与子宫内膜增厚和增生、息肉和癌症的发生率增加有关。近期研究已经确定了涉及跨越G蛋白偶联受体的7-跨膜的新途径接受SERM/SERD治疗的患者的GPER。GPER的交叉反应性药理兴奋性有助于激素抵抗和子宫的非靶点效应，因为所有临床批准的抗- 雌激素作为GPER的激动剂，刺激这些途径。ER/GPER的这一关键问题 SERM和SERD药物的开发没有涉及选择性问题。在我们之前的工作中，我们发现并表征了不结合ERa或ERb的新型GPER选择性配体。最近，我们发现了一种新的小分子，可以在不受GPER干扰的情况下首次靶向ER。由于目前的抗雌激素药物不区分era/b和GPER，我们新发现的小分子提供了创造新的配体和治疗剂来选择性靶向Era的机会。通过对这种第一代时代选择性化合物进行化学修饰，我们改进了亲和力、受体选择性和拮抗剂/激动剂特征，最终目标是创造真正的时代- 选择性的拮抗剂。本方案的具体目的是：1.合成和拆分生物活性物质优化的具有GPER反选择性的Era靶向AB-SERD化合物对映体；2.优先排序通过受体结合、细胞信号传递、增殖和毒性等体外方法合成化合物 3.体内测定铅化合物的抗肿瘤和ADMET性质，使用ER依赖和抗激素抗性转基因、异种移植和PDX肿瘤。这些研究的成功完成将确定创新的对映专一性化合物为独特的药理学工具，用于描述ER和GPER的单独功能，并启动开发一流的治疗药物，目标是减少抗激素耐药复发乳腺癌，每年提高20多万妇女的存活率和生活质量被诊断为ER阳性乳腺癌。！“#$%&‘()*++，”-./01’“，&‘(！，2%(3(