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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：
8137043
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/8137043
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（NR）介导基本的生理过程，但也涉及人类疾病。虽然NR活性受到高度调节，但几乎所有现有的治疗NR依赖性的方法都是通过调节NR活性来实现的。疾病的目标只有一个调节机制，配体结合。基于配体的疗法受到以下限制：获得性耐药性和与非疾病患者正常NR活性改变相关的副作用组织.我的长期目标是为NR依赖性疾病开发新的非配体治疗方法，克服这些限制。我目前的工作重点是雄激素受体（AR），一个典型的NR，它与许多疾病有关，包括前列腺癌（PCa）。目前的抗雄激素治疗可抑制AR 在所有AR表达组织中的活性，导致严重的副作用，并在3-5天后产生耐药性。多年的治疗。正交方法，那些寻求通过配体以外的方式抑制AR活性的方法结合，有可能克服这些局限性，并提供一个重要的治疗补充。基于配体和非配体依赖性抑制剂的联合治疗可以延迟或预防阻力此外，创造组织选择性，非配体抑制剂可以减少相关的副作用目前的抗雄激素治疗。我发明了一种基于细胞的检测方法，使用荧光共振能量转移（FRET）检测AR的构象变化。我用这个实验鉴定抑制AR构象变化和随后转录的新的非配体分子活动最有前途的化合物，pyrvinium双羟萘酸，是一种FDA批准的药物，我已经证明，在小鼠中有效的抗雄激素作用和可能的细胞选择性活性。在这项拨款中，我建议确定细胞选择性PP作用的机制基础，并将这些发现与组织选择性相关联 in vivo.我的目标还在于通过使用细胞因子来大大扩展我们对AR活性的细胞控制的理解。构象变化分析，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点和抗雄激素开发的新线索。