Ligand-Independent Selective Modulation of Androgen Receptor Activity

雄激素受体活性的配体独立选择性调节

基本信息

批准号：
8319654
负责人：
JEREMY O JONES
金额：
$ 24.15万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8319654
关键词：
Adrenergic Receptor Adverse effects Affect Affinity Agonist Amino Acids Androgen Antagonists Androgen Receptor Androgen Response Element Androgens Animal Model Animals Antiandrogen Therapy Anticoagulants Arginine Binding Biochemical Bioinformatics Biological Biological Assay Biological Models Boutos Cancer Patient Caring Castration Cell Culture Techniques Cells Chemistry Cities Clinical Clinical Trials Coagulation Process Complement Core Facility Data Development Disease Disease Resistance Dissection Drug Delivery Systems Enzymes Epidermal Growth Factor Receptor Epithelial Cells FDA approved Failure Family Fluorescence Resonance Energy Transfer Future Gene Expression Genes Genetic Genetic Screening Genetic Transcription Goals Grant Growth Factor Hormones Human In Vitro Incidence Instruction Investigation Lead Ligand Binding Ligands Light Male Pattern Baldness Malignant Neoplasms Malignant neoplasm of prostate Measurement Measures Mediating Methods Metric Modeling Molecular Molecular Biology Molecular Conformation Mus Nuclear Hormone Receptors Nursing Faculty PAPP PTEN gene Paper Pathway interactions Patients Pharmaceutical Preparations Phosphorylation Physiological Physiological Processes Plague Polycystic Ovary Syndrome Population Positioning Attribute Post-Translational Protein Processing Progress Reports Prostate Prostatic Diseases Proteins Pyrvinium pamoate RNA Radiolabeled Rattus Receptor Signaling Recurrence Regulation Relapse Replacement Therapy Reporting Reproducibility Resistance Resistance development Resolution Rodent Model Role Running Sampling Signal Transduction Smooth Muscle Source Stable Isotope Labeling Stromal Cells Testing The Sun Therapeutic Time Tissue Banking Tissue Banks Tissues Translations Validation Vascular Endothelial Growth Factor Receptor Vitamin K Warfarin Work Writing base cancer recurrence carboxylate carboxylation cell type chemical addition chemical genetics clinically relevant combinatorial experience feeding genetic regulatory protein human FRAP1 protein human disease human tissue improved in vivo inhibitor/antagonist interest knock-down member novel patient population pre-clinical prevent prospective radiotracer receptor research study response small molecule tumor progression vitamin K epoxide reductase

项目摘要

Nuclear hormone receptors (NRs) mediate essential physiological processes, but are also implicated in human disease. Though NR activity is highly regulated, nearly all existing approaches to treat NR-dependent disease target only one regulatory mechanism, ligand binding. Ligand-based therapies are limited by acquired resistance and side-effects associated with the alteration of normal NR activity in non-diseased tissue. My long term goal is to develop novel, non-ligand treatments for NR-dependent diseases that overcome these limitations. My current work focuses on the androgen receptor (AR), a canonical NR that is involved in many diseases, including prostate cancer (PCa). Current anti-androgen treatments inhibit AR activity in all AR-expressing tissues, resulting in serious side-effects, and development of resistance after 3-5 years of treatment. Orthogonal approaches, those that seek to inhibit AR activity by means other than ligand binding, have the potential to overcome these limitations and offer an important therapeutic complement. Combinatorial treatment with ligand-based and ligand-independent inhibitors could delay or prevent resistance. Additionally, creating tissue-selective, non-ligand inhibitors could reduce side-effects associated with current anti-androgen treatments. I have created a cell-based assay that measures the ligand-induced conformation change of AR using fluorescence resonance energy transfer (FRET). I used this assay to identify novel, non-ligand molecules that inhibited AR conformation change and subsequent transcriptional activity. The most promising compound, pyrvinium pamoate, is an FDA-approved drug that I have shown has potent anti-androgenic effects in mice and possible cell-selective activity. In this grant, I propose to determine the mechanistic basis of cell-selective PP action and correlate these findings with tissue-selectivity in vivo. I also aim to greatly expand our understanding of the cellular control of AR activity using the conformation change assay to dissect the cellular networks that regulate tissue-selective AR conformation change, thus identifying clinically relevant drug targets and new leads for anti-androgen development.

核激素受体（NRS）介导了基本的生理过程，但也与人类疾病。尽管NR活动受到高度调节，但几乎所有现有的处理NR依赖性方法疾病仅针对一种调节机制，配体结合。基于配体的疗法受到限制获得的抗药性和与非预期正常NR活性改变相关的副作用组织。我的长期目标是为NR依赖性疾病开发新颖的非配体治疗方法克服这些限制。我目前的工作着重于雄激素受体（AR），这是一种规范的NR 涉及许多疾病，包括前列腺癌（PCA）。当前的抗雄激素治疗抑制AR 在所有表达AR的组织中的活性，导致严重的副作用，并在3-5之后发展阻力多年治疗。正交方法，那些试图通过配体以外的其他方式抑制AR活性的方法绑定，有可能克服这些局限性并提供重要的治疗补体。与基于配体和配体无关的抑制剂结合治疗可能会延迟或预防反抗。此外，创建组织选择性的非配体抑制剂可以减少相关的副作用与当前的抗雄激素治疗。我创建了一个基于细胞的测定法，以测量配体诱导的使用荧光共振能量转移（FRET）对AR的构象变化。我用这个测定法识别抑制AR构象变化和随后转录的新型非配体分子活动。我显示的最有前途的化合物是pamoate pamoate，是FDA批准的药物在小鼠和可能的细胞选择活性中有效的抗雄激素作用。在这笔赠款中，我建议确定细胞选择性PP作用的机械基础，并将这些发现与组织选择性相关联体内。我还旨在大大扩展我们对AR活性的细胞控制的理解构象变化测定法，以剖析调节组织选择性AR构象的细胞网络变化，从而确定临床相关的药物靶标和抗雄激素发展的新铅。