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

描述(申请人提供)：项目摘要/摘要：这项工作的长期目标是开发新的前列腺癌药物，以克服目前市场上销售的抗雄激素药物(雄激素是男性性激素)的耐药性。这项拟议工作的具体目标是识别新的先导化合物，这些化合物的作用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。但与目前的药物不同，我们的药物是雄激素与雄激素受体结合的竞争性拮抗剂，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、基于细胞的分析和晶体结构测定，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。虚拟筛选需要获得目标蛋白质的原子分辨率3D结构，它提供了一种成本效益高的方法来筛选数百万种化合物，以识别仅需购买的几种化合物，并在生物或生化分析中进行测试。我们获得了雄激素受体配体结合域的3D结构，这使得这项工作成为可能。这项工作的具体目的是：1.利用虚拟筛选方法筛选数百万个化合物，以正确对接到雄激素受体共调节位点，如我们的雄激素受体配体结合域的原子分辨率3D结构所定义的那样。2.选择并购买数百种具有药物性质且具有较高肠道吸收潜力的化合物。3.在基于细胞的测试中测试这些化合物是否有可能干扰转录激活，并选择最好的化合物。4.通过对雄激素受体的配基结合域的晶体结构测定，确认所选化合物与所选化合物结合在共同调节部位。完成这项提案中概述的具体目标将为先导优化和新型前列腺癌药物的潜在开发提供基础。项目简介：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。尽管目前市场上的药物可以成功地治疗前列腺癌，但这些药物中的大多数在治疗几年后就会失效。我们的目标是开发新的前列腺癌药物，以克服目前市场上销售的药物的耐药性。

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.