Ligand-Independent Selective Modulation of Androgen Receptor Activity

核激素受体(NRs)介导重要的生理过程，但也与 人类疾病。尽管NR活性受到高度调控，但几乎所有现有的治疗NR依赖的方法 疾病只针对一种调节机制，即配体结合。基于配体的治疗受到以下因素的限制 与正常NR活性改变相关的获得性抵抗力和副作用 组织。我的长期目标是开发治疗天然药物依赖型疾病的新的非配体疗法 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AR 在所有AR表达的组织中都有活性，导致严重的副作用，并在3-5年后发展为耐药 多年的治疗。正交方法，寻求通过配体以外的方法抑制AR活性的方法 具有约束力，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迟或预防 抵抗。此外，创造组织选择性的非配基抑制剂可以减少相关的副作用。 目前的抗雄激素治疗。我已经创造了一种基于细胞的分析方法，它可以测量配体诱导的 用荧光共振能量转移(FRET)研究AR的构象变化。我用这个化验方法 识别抑制AR构象变化和随后转录的新的非配体分子 活动。最有希望的化合物，帕莫酸吡喃，是fda批准的药物，我已经展示了 对小鼠的强大的抗雄激素作用和可能的细胞选择活性。在这笔赠款中，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 在活体内。我的目标也是大大扩展我们对细胞控制AR活动的理解 构象变化分析法剖析调节组织选择性AR构象的细胞网络 改变，从而确定临床相关的药物靶点和抗雄激素开发的新线索。

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.