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）：抑制前列腺癌（CRPC）是一种无法治愈的疾病，需要对这种疾病进行新颖和有效的疗法。 CRPC仍取决于雄激素受体（AR）转录活性的持续生长和存活。 CRPC的当前和研究疗法直接或间接地靶向AR的配体结合结构域（LBD），但是反式激活和DNA结合结构域（TAD和DBD）尚未被用作治疗靶标。为了鉴定新型的AR转录抑制剂，我们设计了一个高吞吐量酵母单杂交药物筛选（AIM 1），其中报告基因表达取决于缺乏功能性LBD的AR缺失突变体的组成型转录活性。在这个系统中，抑制报告基因活性指示了一种推定的AR转录抑制剂，该抑制剂会干扰TAD和/或DBD功能。因此，我们的测定法将有利于鉴定针对TAD和/或DBD的所需化合物组，并提供克服cast割抵抗力的承诺。我们的酵母单杂交筛选测定法的鲁棒性已经建立（z'> 0.5），并且已经设计了反屏幕，以排除非特殊抑制报告基因活性的化合物。在我们的酵母单杂交筛选中鉴定的化合物的AR抑制特性将在多个依赖AR依赖性的哺乳动物系统中进行测试（AIM 2）。接下来，将评估化合物的体外抗肿瘤活性（AIM 3）。最活跃的药物将经历结构活动关系（SAR）分析，然后在重复过程中重复对生化和体外生物学活性进行重复测试，其目的是识别两种铅优化化合物，以评估评估抗神经性生物学活性在体内的体内化合物。依赖AR的CRPC小鼠模型（AIM 3）。然后，我们将评估在AR依赖性CRPC模型中具有选择性在体内抗肿瘤活性的化合物的抗AR作用的潜在机制（AIM 4）。在成功执行拟议工作之后，我们的目标是选择铅优化的AR转录抑制剂，以快速转化为转移性CRPC患者的早期PHAS人类试验。