Identification of Novel Androgen Receptor Antagonists for the Treatment of Hormon

用于治疗激素的新型雄激素受体拮抗剂的鉴定

基本信息

批准号：
7744558
负责人：
JOHN D NORRIS
金额：
$ 22.34万
依托单位：
INTEGRATED ONCOLOGY SOLUTIONS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-20 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7744558
关键词：
Accessory Sex Organs Adolescence Agonist Androgen Antagonists Androgen Receptor Androgens Arts Bacteriophage T7 Binding Biological Biological Assay Breast Cancer Treatment Cancer Cell Growth Cancer Patient Cells Characteristics Chemistry Classification Collaborations Dependence Development Discrimination Disease Disease Progression Effectiveness Estrogen Receptors Evolution Exhibits Expression Library Face Faslodex(ICI 182,780)Funding Goals Growth Hair Hormonal Hormones In Vitro Knowledge Lead Ligand Binding Ligands Link Maintenance Malignant Neoplasms Malignant neoplasm of prostate Measures Mediating Metastatic Prostate Cancer Methodology Modeling Molecular Molecular Conformation Molecular Mechanisms of Action Nature Nuclear Receptors Patients Phage Display Pharmacology Phase Phase I Clinical Trials Pre-Clinical Model Process Production Prostate Prostate Cancer therapy Proteins Refractory Refractory Disease Relapse Reporter Genes Resistance Resistance development Screening procedure Structure System Technology Testing Testosterone Tissues Two-Hybrid System Techniques Validation advanced disease base cDNA Expression cofactor commercialization design drug discovery experience gland development hormone refractory prostate cancer hormone therapy human RIPK1 protein insight interest male muscle form next generation novel novel strategies overexpression programs protein protein interaction public health relevance receptor selective androgen receptor modulator therapy design tool transcription factor tumor tumor growth

项目摘要

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.

描述（由申请人提供）：晚期前列腺癌患者通常接受激素治疗以阻止雄激素产生（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很普遍，导致激素难治性前列腺癌。尽管这种激素 - 侵犯状态，但肿瘤仍保留对AR生长的依赖。实际上，最近的研究表明，AR过表达是向激素难治状态发展的关键步骤。因此，鉴定新的抗雄激素，旨在抑制AR过表达的系统中前列腺癌细胞的生长，这是设计这种疾病的新型疗法的重要一步。传统上，AR拮抗剂是以经验方式鉴定的，化学主要由体外配体结合测定引导，然后是测量功能拮抗作用的次级转录报告基因测定。但是，这些方法已经成功，但是，经过临床认可的抗多蛋白似乎是机械上相似的，并且表现出部分激动剂活性，从而限制了它们在治疗激素难治性疾病中的有效性。下一代抗多蛋白的合理设计将需要更复杂的筛选方法。在此阶段1计划中，我们将采用一种新型策略来通过利用我们当前对AR作用分子决定因素的理解的方法来解决这一重要问题，并观察到，核受体药理学在很大程度上是通过这些转录因子以差异方式与任何转录共激活剂或转录仪或共染色器相互作用的能力来介导的。我们将使用优化的T7噬菌体显示技术来对与拮抗剂绑定的AR相互作用的蛋白质进行全面的屏幕。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），该工具将使我们能够识别能够使差异辅助相互作用的化合物。使用此工具，我们将尝试识别几种机械上不同的抗雄激素，其中一些可以预测可极大地抑制AR活性并有效抑制激素难治性肿瘤的生长。在雌激素受体场中，事实证明，这种性质（Faslodex（R））的化合物对乳腺癌的治疗很有用，乳腺癌已成为第一线激素治疗的难治性。该提案的既定目标是产生能够区分机械上不同抗dro剂的RCPT。 RCPT的有效性将通过评估其预测雄激素依赖性和非依赖性疾病的临床前模型中化合物活性的能力来测试。然后，从这一第一阶段研究中获得的见解将用于优化新型的铅化合物，以在针对商业化的2阶段资助期内治疗激素难治性前列腺癌。公共卫生相关性：通过雄激素受体（AR）起作用的雄激素不仅负责正常的次要性特征的发展和维持（性配饰器官的增长，身体和面部毛发的生长，肌肉的增长，肌肉质量的增加，肌肉质量的增长），而且对男性的青春期相关，而且对前列腺的发育和有效的疾病是至关重要的。实际上，前列腺癌通常对靶向雄激素产生或AR本身的激素疗法有反应。但是，通过通常导致AR活性增强的机制，对当前可用的疗法的抗性会产生，并且癌症发展为激素不良状态。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能够鉴定出与当前使用的AR拮抗剂不同的新型抗雄激素的新型药物发现工具。该阶段1项目的成功完成将允许实施该新型筛选工具，以在发现和验证新类别的机械独特AR拮抗剂的新类别中，预计在2期资金期间将在激素难治疾病中具有功效。