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

• 批准号: 7638779
• 负责人: JEREMY O JONES
• 金额: $ 11.6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-06-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7638779
• 关键词: Accounting; Adverse effects; Androgen Antagonists; Androgen Receptor; Antiandrogen Therapy; Attention; Biological Assay; Cells; Chemicals; Collaborations; Collection; Complement; Computer software; Data Set; Development; Disease; Dissection; Drug Delivery Systems; FDA approved; Fluorescence Resonance Energy Transfer; Gene Expression; Genes; Genetic; Goals; Grant; In Vitro; Institutes; Libraries; Ligand Binding; Ligands; Malignant Neoplasms; Malignant neoplasm of prostate; Mass Spectrum Analysis; Measurement; Measures; Mediating; Microscopy; Modification; Molecular; Molecular Conformation; Mus; Nuclear; Nuclear Hormone Receptors; Nuclear Translocation; Ontology; Pathway interactions; Pattern; Pharmaceutical Preparations; Physiological; Physiological Processes; Plague; Principal Investigator; Prostate; Proteins; Pyrvinium pamoate; Receptor Signaling; Resistance; Resistance development; Small Interfering RNA; Therapeutic; Tissues; Training; Validation; Work; analog; base; career; cellular targeting; chemical genetics; clinically relevant; combinatorial; crosslink; genome-wide; human disease; in vivo; inhibitor/antagonist; kidney cell; link protein; novel; prevent; small molecule

DESCRIPTION (provided by applicant): Nuclear hormone receptors (NRs) mediate essential physiological processes, but are also implicated in human disease. Though NR activity is highly regulated, nearly ail 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-disease 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 PCa develops 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. RELEVANCE: This work is directly applicable to prostate cancer and other diseases related to androgen receptor signaling. I will identify new ways to selectively control the activity of the androgen receptor in order to prevent the development of resistance in cancers and the harmful side-effects that plague current anti-androgen therapies.

描述(由申请人提供)：核激素受体(NRs)调节基本的生理过程，但也与人类疾病有关。尽管NR活性受到高度调控，但几乎所有现有的治疗NR依赖疾病的方法都只针对一种调节机制，即配体结合。基于配体的治疗受到获得性耐药性和与非疾病组织中正常NR活性改变相关的副作用的限制。我的长期目标是开发新的、非配体治疗NR依赖疾病的方法，以克服这些限制。我目前的工作重点是雄激素受体(AR)，这是一种典型的雄激素受体，与许多疾病有关，包括前列腺癌(PCA)。目前的抗雄激素治疗抑制了所有AR表达组织中的AR活性，导致了严重的副作用，PCA在治疗3-5年后产生耐药性。正交方法，即那些寻求通过配体结合以外的方法抑制AR活性的方法，有可能克服这些限制，并提供重要的治疗补充。以配体为基础的和非配体非依赖的抑制剂的联合治疗可以延缓或防止耐药性。此外，创造组织选择性的非配体抑制剂可以减少与目前的抗雄激素治疗相关的副作用。我已经创建了一种基于细胞的分析方法，使用荧光共振能量转移(FRET)来测量配体诱导的AR构象变化。我用这种方法鉴定了抑制AR构象变化和随后的转录活性的新的非配体分子。最有希望的化合物是甲酸吡喃，这是FDA批准的一种药物，我已经证明了它在小鼠身上具有强大的抗雄激素作用和可能的细胞选择活性。在这项资助中，我建议确定细胞选择性PP作用的机制基础，并将这些发现与体内组织选择性相关联。我的另一个目的是通过构象变化分析来剖析调节组织选择性AR构象变化的细胞网络，从而确定临床相关的药物靶点和抗雄激素开发的新线索，从而极大地扩大我们对AR活性的细胞控制的理解。 相关性：这项工作直接适用于前列腺癌和其他与雄激素受体信号转导相关的疾病。我将找到有选择地控制雄激素受体活性的新方法，以防止癌症耐药性的发展和困扰当前抗雄激素疗法的有害副作用。