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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(

! ! ! ! 项目摘要激素疗法在治疗雌激素受体阳性的妇女方面具有革命性意义 (ER+）乳腺癌，大大提高生存率。ER靶向激素治疗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剂雌激素受体拮抗剂（SERD），如氟维司群，而芳香酶抑制剂阻断雌激素的生物合成。这些治疗具有显著的副作用，并且它们的长期使用可导致约一个- 三分之一的接受治疗的妇女，往往导致更积极的癌症。此外，他莫昔芬的使用是与子宫内膜增厚和增生、息肉和癌症的发病率增加有关。最近研究已经确定了涉及7跨膜G蛋白偶联受体的新途径接受SERM/SERD治疗的患者的GPER。GPER的交叉反应药理学激动作用有助于子宫内的激素抵抗和脱靶效应，因为所有临床批准的抗- 雌激素作为GPER的激动剂并刺激这些途径。ER/GPER的这一关键问题选择性在SERM和SERD药物的开发中尚未得到解决。在以前的工作中，我们发现并表征了不结合ERa或ERb的GPER的新型选择性配体。发现了一种新的小分子，首次靶向ER而不受GPER的干扰。由于目前的抗雌激素药物不能区分ER a/B和GPER，我们新鉴定的小分子提供了创造选择性靶向ER α的新型配体和治疗剂的机会。通过对这种第一代ER α选择性化合物的化学修饰，我们已经改善了亲和力、受体选择性和拮抗剂/激动剂特性，最终目标是产生真正的ER α- 选择性拮抗剂这项建议的具体目标是：1.合成并解析生物活性具有GPER抗选择性的优化的ER α靶向AB-SERD化合物的对映异构体; 2.优先考虑化合物通过体外方法，包括受体结合、细胞信号传导、增殖和毒性， 3.使用ER依赖性和ADMET测定先导化合物的体内抗肿瘤和ADMET性质。抗激素耐药转基因、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体特异性化合物，独特的药理学工具，用于描述ER和GPER的个体功能，并启动开发一流的治疗药物，目的是减少抗激素抵抗复发乳腺癌，提高生存率和生活质量，每年超过20万妇女被诊断为ER阳性乳腺癌 ! "#$%&'()*++,"-./ 01'"，&'（！，2%（3）