Partial Agonists at Estrogen Receptor alpha for Breast Cancer Therapy

用于乳腺癌治疗的雌激素受体α部分激动剂

基本信息

批准号：
9251781
负责人：
Gregory R. J Thatcher
金额：
$ 47.43万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-06 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9251781
关键词：
Adverse effects Affinity Agonist Androgen Receptor Animal Model Animals Apoptosis Benchmarking Binding Biological Assay Biological Availability Breast Breast Cancer Cell Breast Cancer Treatment Breast Cancer therapy Breast Epithelial Cells Cell Line Cell Survival Cells Chemicals Chemistry Chemoprevention Clinical Collection Computer-Aided Design Computing Methodologies Data Data Correlations Development Diethylstilbestrol Drug Targeting Endometrial Endometrial Carcinoma Endometrium Estradiol Estrogen Antagonists Estrogen Receptor Modulators Estrogen Receptor Status Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogens Europe Exposure to Female Fluorescence Resonance Energy Transfer Future Generations Genes Growth Gynecology Human In Vitro Indoles Lead Libraries Ligand Binding Domain Ligands Link Liver Microsomes MCF7 cell MDA MB 231 Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Mammary gland Measurement Measures Messenger RNA Metabolism NCOA3 gene Oral PRKCA gene Parents Patients Pharmaceutical Preparations Pharmacology Phenotype Plasma Postmenopausal Osteoporosis Progesterone Receptors Proteins Proteomics Pyrazoles Raloxifene Reporter Resistance Resistance development Risk Safety Selective Estrogen Receptor Modulators Structure T47D TFF1 gene Tamoxifen Testing Therapeutic Therapeutic Agents Therapeutic Index Tissues Transcription Factor AP-1 Uterus Validation Woman Women&apos s Health Xenograft Model Xenograft procedure base benzothiophene bone cancer risk chemotherapy counterscreen design drug development drug metabolism effective therapy epidemiology study estrogenic exhaustion experience improved in vivo in vivo Model iterative design lead series malignant breast neoplasm mortality neglect novel novel therapeutics oncology outcome forecast overexpression personalized medicine prototype public health relevance radioligand receptor receptor function response scaffold screening small molecule standard of care success survivin three dimensional cell culture tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): The estrogen receptor (ER) is a drug target that has been exploited clinically by selective estrogen receptor modulators (SERMs) that antagonize estrogenic effects in breast tissue and act as agonists in bone. The proto- type of the SERM drug class, tamoxifen (TAM) has for 3 decades been the standard of care in breast cancer therapy, although agonist activity in the uterus increases risk of endometrial cancer. Conversely, the therapeutic potential of ERa agonists has not been explored or exploited. Up to 80% of breast cancers are ER+, in which estradiol (E2) fuels tumor growth. Of these, 30-50% are unresponsive to TAM or develop resistance, leaving few treatment options. Paradoxically, prior to the introduction of TAM, both E2 and the ER agonist diethylstilbestrol achieved success in the treatment of breast cancer, but with unacceptable side effects, including agonist activity in breast and uterus. A partial agonist at ERa without estrogenic actions in normal gynecological tissues, but with the ability to regress TAM-resistant cancers is a compelling concept, validated by us in 2 animal models with 2 small molecules. The assembled team at UI, Greg Thatcher, John Katzenellenbogen, Terry Moore, and Deb Tonetti has all assays and chemistry in place to achieve the proposed aims: Aim 1. A library of ~350 com- pounds consisting of 4 lead series will be completed and screened using a FRET assay for SRC3 co-activator binding to ERa and ERß. The ER interaction with co-activator is seen as the minimal predictor of phenotype. Radioligand displacement for ER represents a secondary, confirmatory assay. Partial agonists at ERa with agonist/inactive responses at ERß will be obtained and iteratively optimized using data from Aim 2 to provide SAR development for computer-aided design. Aim 2. Selected ERa agonists from FRET screening will be studied using reporter assays in endogenous ERa (MCF-7; T47D) and in ERß (ß43) mammary epithelial cells and endometrial cells to reveal potency, and agonist/antagonist pharmacology. Partial agonists will be further studied using PCR measurement of ERE, AP-1, and Sp1-sensitive genes. The primary phenotypic assay is apoptosis of TAM-resistant MCF7-5C cells. Counterscreens are proliferation of parent MCF7-5C and T47D cell lines. Aim 3. Drug metabolism in liver microsomes, multiplex CYP-inhibition, and oral plasma bioavailability will be used to refine ERa partial agonists as chemical probes. Our extensive experience with SERM metabolism and use of oral delivery in all preliminary data gives confidence in this approach. DMPK studies will provide final selection for animal studies. Three different TAM-resistant xenograft models will be used to test chemical probes and to determine therapeutic index for tumor regression. Safety will be predicted by uterine growth and parallel study of growth of estrogen-dependent T47D xenografts. Supportive mechanism of action studies are limited to ERa localization and target selectivity proteomics. Completion of these Aims will provide chemical probes to study the potential of novel partial agonists and allosteric modulators of ER function, and provide lead compounds for future testing in patient-derived xenografts of PKCa-overexpressing tumors as a prelude to drug development.

描述（由应用提供）：雌激素受体（ER）是一种药物靶标，已通过选择性雌激素受体调节剂（SERM）在临床上探索，在乳腺组织中拮抗雌激素作用并充当骨骼中的激动剂。 Serm药物类的原型型他莫昔芬（TAM）已有30年来一直是乳腺癌疗法的护理标准，尽管子宫中的激动剂活性增加了子宫内膜癌的风险。相反，尚未探索或探索ERA激动剂的治疗潜力。多达80％的乳腺癌为ER+，其中雌二醇（E2）促进肿瘤的生长。其中30-50％对TAM或发育耐药性无反应，几乎没有治疗选择。矛盾的是，在引入TAM之前，E2和ER激动剂二乙基贝特罗尔在治疗乳腺癌方面取得了成功，但具有不可接受的副作用，包括乳腺癌和子宫中的激动剂活性。在正常妇科组织中没有雌激素作用的ERA的部分激动剂，但具有退缩抗TAM抗TAM的癌症的能力是一个令人信服的概念，在2个具有2个小分子的动物模型中，我们证实了我们的验证。 UI，Greg Thatcher，John Katzenellenbogen，Terry Moore和Deb Tonetti的组装团队都有所有的测定和化学反应，以实现拟议的目标：AIM1。AIM1。〜350 com- compoungs的图书馆，由4个领先系列组成的〜350 compounds将通过SRC3 Co-Activ Activativator binding binding to Ercom和Er-Er-Er-Er-Er-Er-Ercom和Er-Er-er-er-Erscome完成和筛选。与共激活因子的ER相互作用被视为表型的最小预测指标。 ER的放射性置换代表了次要的，确认的测定法。将在ERß处具有激动剂/非活动反应的ERA的部分激动剂，并使用AIM 2的数据进行迭代优化，以提供计算机辅助设计的SAR开发。 AIM 2。从FRET筛选中选定的ERA激动剂将使用内源性时代（MCF-7； T47D）和ERß（ß43）乳腺上皮细胞和子宫内膜细胞中的记者测定法进行研究，以揭示效力，以及激动剂/拮抗剂药理学。使用ERE，AP-1和SP1敏感基因的PCR测量，部分激动剂将进一步研究。主要的表型测定是抗TAM MCF7-5C细胞的凋亡。计数屏是父级MCF7-5C和T47D细胞系的增殖。 AIM 3。肝微粒体中的药物代谢，多种CYP抑制和口服血浆生物利用度将用于改善局部ERA局部激动剂作为化学问题。我们在Serm代谢方面的丰富经验和在所有初步数据中使用口服交付的经验使这种方法充满信心。 DMPK研究将为动物研究提供最终选择。将使用三种不同的TAM耐药异种移植模型来测试化学问题并确定肿瘤消退的治疗指数。子宫生长和雌激素依赖性T47D异种移植物的生长的平行研究将预测安全性。作用研究的支持机制仅限于ERA定位和靶向选择性蛋白质组学。这些目的的完成将提供化学问题，以研究新型部分激动剂和ER功能的变构调节剂的潜力，并为在患者衍生的非洲PKCA过表达肿瘤的异种移植物中提供铅化合物，以此作为药物发育的前奏。