Identification of Inhibitors of the N-Terminal Region of the Androgen Receptor

雄激素受体 N 末端区域抑制剂的鉴定

基本信息

批准号：
8699713
负责人：
MATTHEW B RETTIG
金额：
$ 25.36万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-26 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8699713
关键词：
Androgen Antagonists Androgen Receptor Androgen Response Element Androgens Bicalutamide Biochemical Biochemistry Biological Biological Assay Biological Models C-terminal Cancer Patient Castration Cells Characteristics Chemicals Clinic DNA Binding Domain Development Disease Drug Targeting Ectopic Expression Environment Exhibits Gene Expression Goals Gonadotropin-Releasing Hormone Analog Growth Hormonal Hormones Human Hybrids In Vitro Investigational Therapies Lead Leuprolide Libraries Ligand Binding Domain Literature Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Mammalian Cell Messenger RNA Mixed Function Oxygenases Molecular Molecular Biology Molecular Target Mus N-terminal New Agents Nuclear Operative Surgical Procedures Patients Pharmaceutical Preparations Phase Preclinical Drug Evaluation Process Property Prostatic Epithelium Proteins Publishing RNA Splicing Receptor Activation Receptor Signaling Reporter Genes Reporting Resistance Serum Specimen Steroid Receptors Steroid biosynthesis Structure-Activity Relationship System Testing Therapeutic Transactivation Translations Variant Wit Work Xenograft Model Yeasts abiraterone base castration resistant prostate cancer clinically significant design effective therapy in vitro testing in vivo inhibitor/antagonist male men mouse model mutant neoplastic neoplastic cell novel novel strategies prostate cancer cell prostate cancer model receptor function response screening small molecule libraries therapeutic target therapy design transcription factor tumor

项目摘要

DESCRIPTION (provided by applicant): Castration resistant prostate cancer (CRPC) is an incurable disease for which novel and effective therapies are critically needed. CRPCs remain dependent upon androgen receptor (AR) transcriptional activity for continued growth and survival. Current and investigational therapies for CRPC directly or indirectly target the ligand binding domain (LBD) of the AR, yet the transactivation and DNA binding domains (TAD and DBD, respectively) have not been exploited as therapeutic targets. To identify novel AR transcriptional inhibitors, we have designed a high throughput yeast one-hybrid drug screen (Aim 1), in which reporter gene expression is dependent upon the constitutive transcriptional activity of a deletion mutant of the AR that lacks a functional LBD. In this system, suppression of reporter gene activity is indicative of a putative AR transcriptional inhibitor that interferes wit TAD and/or DBD function. Thus, our assay will favor the identification of a desired group of compounds that target the TAD and/or DBD and offer the promise of overcoming castration resistance. The robustness of our yeast one-hybrid screening assay has been established (Z' > 0.5), and counter-screens have been designed to exclude compounds that non-specifically inhibit reporter gene activity. The AR inhibitory properties of compounds identified in our yeast one-hybrid screen will be tested in multiple AR-dependent mammalian systems (Aim 2). Next, compounds will be evaluated for in vitro anti-tumor activity (Aim 3). The most active drugs will undergo structure activity relationship (SAR) analysis followed by repeated testing of biochemical and in vitro biologic activity in a reiterative process, the goal of which will be to identify two lead optimized compounds for assessing anti- neoplastic biological activity in vivo in AR-dependent CRPC mouse models (Aim 3). We will then evaluate the underlying mechanism of anti-AR action of compounds that exhibit selective in vivo anti- tumor activity in AR-dependent CRPC models (Aim 4). Our objective subsequent to the successful execution of the proposed work is to select a lead optimized AR transcriptional inhibitor for rapid translation to early phas human trials in patients with metastatic CRPC.

描述（由申请人提供）：去势抵抗性前列腺癌（CRPC）是一种无法治愈的疾病，迫切需要新颖且有效的疗法。 CRPC 的持续生长和存活仍然依赖于雄激素受体 (AR) 转录活性。目前和研究中的 CRPC 疗法直接或间接靶向 AR 的配体结合域 (LBD)，但反式激活域和 DNA 结合域（分别为 TAD 和 DBD）尚未被用作治疗靶点。为了鉴定新型 AR 转录抑制剂，我们设计了一种高通量酵母单杂交药物筛选（目标 1），其中报告基因表达依赖于缺乏功能性 LBD 的 AR 缺失突变体的组成型转录活性。在这个系统中，抑制报告基因活性表明假定的 AR 转录抑制剂干扰 TAD 和/或 DBD 功能。因此，我们的测定将有利于鉴定一组靶向 TAD 和/或 DBD 的所需化合物，并有望克服去势抵抗。我们的酵母单杂交筛选测定的稳健性已经建立（Z'> 0.5），并且设计了反筛选以排除非特异性抑制报告基因活性的化合物。我们的酵母单杂交筛选中鉴定出的化合物的 AR 抑制特性将在多个 AR 依赖性哺乳动物系统中进行测试（目标 2）。接下来，将评估化合物的体外抗肿瘤活性（目标 3）。最活跃的药物将进行结构活性关系（SAR）分析，然后在重复过程中重复测试生化和体外生物活性，其目标是确定两种先导优化化合物，用于评估体内抗肿瘤生物活性在 AR 依赖性 CRPC 小鼠模型（目标 3）。然后，我们将评估在 AR 依赖性 CRPC 模型中表现出选择性体内抗肿瘤活性的化合物的抗 AR 作用的潜在机制（目标 4）。成功执行拟议工作后，我们的目标是选择一种先导优化的 AR 转录抑制剂，以快速转化为转移性 CRPC 患者的早期人体试验。