Identification of Novel Androgen Receptor Antagonists for the Treatment of Hormon

描述（由申请方提供）：晚期前列腺癌患者通常接受激素治疗，以阻断雄激素产生（LHRH激动剂）和/或阻断雄激素受体（AR）活性（抗雄激素）。不幸的是，对激素治疗的耐药性的发展是常见的，导致前列腺癌的难治性。尽管存在这种难治性状态，但肿瘤仍依赖AR生长。事实上，最近的研究表明，AR过表达是进展到难治性状态的关键步骤。因此，新的抗雄激素，旨在抑制前列腺癌细胞生长的系统中，AR是过表达的鉴定，是一个重要的步骤，在设计新的疗法治疗这种疾病。传统上，AR拮抗剂已经以经验的方式鉴定，其中化学主要通过体外配体结合测定来指导，然后通过测量功能性拮抗作用的二级转录报告基因测定来指导。这些方法是成功的，然而，临床上批准的抗雄激素似乎在机制上是相似的，并表现出部分激动剂活性，限制了它们在治疗难治性疾病中的有效性。下一代抗雄激素药物的合理设计将需要更复杂的筛选方法。在这个第一阶段计划中，我们将采用一种新的策略来解决这个重要的问题，通过使用一种方法，利用我们目前对AR作用的分子决定因素的理解，并观察到核受体药理学在很大程度上是由这些转录因子以不同的方式与转录共激活因子或共抑制因子相互作用的能力介导的。我们将使用优化的T7噬菌体展示技术来进行与拮抗剂结合的AR相互作用的蛋白质的全面筛选。然后，这些相互作用的蛋白质将用于开发“受体构象分析工具”（RCPT），这将使我们能够识别能够实现差异辅因子相互作用的化合物。使用这个工具，我们将试图确定几个机制不同的抗雄激素，其中一些可以预测显着抑制AR活性，并有效地抑制肿瘤难治性肿瘤的生长。在雌激素受体领域，这种性质的化合物（芙仕得）已被证明可用于治疗一线激素治疗难治的乳腺癌。该提案的既定目标是产生能够区分机械上不同的抗雄激素的RCPT。RCPT的有效性将通过评估其预测化合物在雄激素依赖性和非依赖性疾病的临床前模型中的活性的能力来测试。从这项1期研究中获得的见解将用于优化新的先导化合物，用于在旨在商业化的2期资助期间治疗难治性前列腺癌。 公共卫生相关性：雄激素如睾酮，通过雄激素受体（AR）起作用，不仅负责与青春期相关的男性正常第二性征（性附属器官的生长，身体和面部毛发的生长，肌肉质量的增加）的发育和维持，而且对前列腺发育也至关重要，并与前列腺癌的进展有因果关系。事实上，前列腺癌通常最初对靶向雄激素产生或AR本身的激素疗法有反应。然而，通过经常导致增强的AR活性的机制，对目前可用的疗法产生抗性，并且癌症进展到难治性状态。我们提出的目标是使用最先进的蛋白质-蛋白质相互作用筛选技术来开发和验证一种新型药物发现工具，该工具能够识别以与目前使用的AR拮抗剂不同的方式发挥作用的新型抗雄激素。该1期项目的成功完成将允许实施这种新型筛选工具，用于发现和验证新类型的机制独特的AR拮抗剂，预计在2期资助期间对难治性疾病有效。

DESCRIPTION (provided by applicant): Patients with advanced prostate cancer typically undergo hormonal therapy to block androgen production (LHRH agonist) and/or block androgen receptor (AR) activity (antiandrogens). Unfortunately, development of resistance to hormonal treatments is common, resulting in hormone-refractory prostate cancer. Despite this hormone-refractory state, tumors retain dependence upon the AR for growth. Indeed, recent studies suggest that AR overexpression is a critical step in the progression to a hormone-refractory state. Thus, the identification of new antiandrogens, designed to inhibit prostate cancer cell growth in systems where AR is overexpressed, is an important step in the design of novel therapies for the treatment of this disease. Traditionally, AR antagonists have been identified in an empirical manner with chemistry being guided primarily by in vitro ligand binding assays, followed by secondary transcriptional reporter gene assays that measure functional antagonism. These approaches have been successful, however, the clinically approved antiandrogens appear to be mechanistically similar and exhibit partial agonist activity that limits their effectiveness in treating hormone-refractory disease. The rational design of next generation antiandrogens will require more sophisticated screening methodologies. During this Phase 1 program, we will employ a novel strategy to tackle this important problem by using an approach that takes advantage of our current understanding of the molecular determinants of AR action and the observation that nuclear receptor pharmacology is mediated in large part by the ability of these transcription factors to interact in a differential manner with either transcriptional co-activators or co-repressors. We will use an optimized T7 phage display technology to perform a comprehensive screen for proteins that interact with antagonist bound AR. These interacting proteins will then be used to develop a "receptor conformation profiling tool" (RCPT) that will allow us to identify compounds that enable differential cofactor interactions. Using this tool, we will attempt to identify several mechanistically distinct antiandrogens, some of which may be predicted to dramatically suppress AR activity and effectively suppress hormone-refractory tumor growth. In the estrogen receptor field, compounds of this nature (Faslodex(R)) have proven to be useful in the treatment of breast cancer that has become refractory to first line hormonal therapy. The stated objective of this proposal is to generate a RCPT capable of discriminating between mechanistically distinct antiandrogens. The validity of the RCPT will be tested by assessing its ability to predict the activity of compounds in pre-clinical models of androgen-dependent and -independent disease. Insights gained from this Phase 1 study will then be used to optimize novel lead compounds for the treatment of hormone-refractory prostate cancer in a Phase 2 funding period aimed at commercialization. PUBLIC HEALTH RELEVANCE: Androgens like testosterone, acting through the androgen receptor (AR), are not only responsible for the development and maintenance of the normal secondary sexual characteristics (growth of sex accessory organs, body and facial hair growth, increase in muscle mass) associated with adolescence in males, but are also critical for prostate gland development and are causally linked to the progression of prostate cancer. Indeed, prostate cancer is often initially responsive to hormonal therapies targeting androgen production or the AR itself. However, through mechanisms that often result in heightened AR activity, resistance to currently available therapies arises and the cancer progresses to a hormone-refractory state. Our proposed goal is to use state-of-art protein-protein interaction screening technology to develop and validate a novel drug discovery tool capable of identifying novel antiandrogens that function in a different way from currently used AR antagonists. Successful completion of this Phase 1 project will allow the implementation of this novel screening tool for use in the discovery and validation of new classes of mechanistically unique AR antagonists predicted to have efficacy in hormone-refractory disease during a Phase 2 funding period.