Search for Anti-Androgen Compounds to Overcome Resistance of Current Drugs

寻找抗雄激素化合物以克服现有药物的耐药性

• 批准号: 7154608
• 负责人: Sherin S Abdel-Meguid
• 金额: $ 24.18万
• 依托单位: SHIFA BIOMEDICAL CORPORATION
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-21 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7154608
• 关键词: androgen receptor; androgens; lead; ligands; neoplasm /cancer; prostate neoplasms; proteins; teacher

DESCRIPTION (provided by applicant): Project Summary/Abstract:The long-term goal of this work is to develop new prostate cancer drugs that overcome the resistance seen with current marketed anti-androgen drugs (androgens are male sex hormones). The specific aim of the proposed work is to identify novel lead compounds that work by a different mechanism than that of current drugs. As with current drugs our molecular target will be the androgen receptor. But unlike current drugs that are competive antagonists of androgens' binding to the androgen receptor, our compounds will interfere with the interaction between the androgen receptor and its co-regulator proteins. To that end, we will integrate virtual (computer) screening methods, cell-based assays and crystal structure determinations to identify lead compounds that can potentially be optimized to produce a drug for the treatment of prostate cancer. Virtual screening, which requires the availability of atomic resolution 3D structures of the target protein, provides a cost effective way to screen millions of compounds to identify just a few to be purchased and tested in a biological or biochemical assay. Our access to such 3D structures of the androgen receptor ligand binding domain makes this work possible. The specific aims of this work are to: 1. Utilize virtual screening methods to screen millions of compound for their proper docking into the androgen receptor co-regulator site, as defined by our atomic resolution 3D structures of the androgen receptor ligand binding domain. 2. Select and purchase a few hundred compounds that are "drug like" and have high potential to be intestinally absorbed. 3. Test these compounds in a cell-based assay for their potential to disrupt transcriptional activation, and select the best compounds. 4. Confirm that the selected compounds bind at the co-regulator site using crystal structure determination of the androgen receptor's ligand binding domain in complex with each selected compound. Accomplishing the specific aims outlined in this proposal will provide the foundation for lead optimization and the potential development of novel prostate cancer drugs. Project Narrative: Prostate cancer, which accounts for 10% of male cancer-related deaths in the US, is the second leading cause of cancer death in American men, exceeded only by lung cancer. Although prostate cancer can be successfully treated with current marketed drugs, most of these drugs become ineffective after only a few years of treatment. Our goal is to develop new prostate cancer drugs that overcome the resistance seen with current marketed drugs.

描述（由申请人提供）：项目总结/摘要：这项工作的长期目标是开发新的前列腺癌药物，克服目前市售的抗雄激素药物（雄激素是男性性激素）的耐药性。拟议工作的具体目标是确定新的先导化合物，其工作机制与现有药物不同。与目前的药物一样，我们的分子靶点将是雄激素受体。但是，与目前的药物是雄激素与雄激素受体结合的竞争性拮抗剂不同，我们的化合物将干扰雄激素受体及其辅助调节蛋白之间的相互作用。为此，我们将整合虚拟（计算机）筛选方法，基于细胞的测定和晶体结构测定，以确定可能优化的先导化合物，以生产治疗前列腺癌的药物。虚拟筛选需要靶蛋白的原子分辨率3D结构的可用性，提供了一种具有成本效益的方法来筛选数百万种化合物，以识别仅需购买和在生物或生化测定中测试的几种化合物。我们对雄激素受体配体结合结构域的这种3D结构的访问使这项工作成为可能。本工作的具体目标是：1。利用虚拟筛选方法筛选数百万种化合物，使其正确对接到雄激素受体辅助调节位点，如我们的雄激素受体配体结合结构域的原子分辨率3D结构所定义。2.选择和购买几百种“药物样”的化合物，并有很高的潜力被人体吸收。3.在基于细胞的测定中测试这些化合物破坏转录激活的潜力，并选择最佳化合物。4.通过测定雄激素受体的配体结合域与各选定化合物的复合物的晶体结构，确认选定化合物在共调节位点结合。实现本提案中概述的具体目标将为铅优化和新型前列腺癌药物的潜在开发提供基础。项目叙述：前列腺癌占美国男性癌症相关死亡的10%，是美国男性癌症死亡的第二大原因，仅次于肺癌。虽然前列腺癌可以成功地用目前上市的药物治疗，但这些药物中的大多数在治疗几年后就无效了。我们的目标是开发新的前列腺癌药物，克服目前上市药物的耐药性。