Dynamic, Structure Driven Fragment Based Design of Selective Androgen Modulators

描述(申请人提供)：这项工作的长期目标是开发新的药物，目标是治疗晚期前列腺癌，克服所有前列腺癌对现有抗雄激素药物产生抗药性的能力。这些变化导致预后不良，对晚期前列腺癌的成功治疗构成了重大的临床挑战。前列腺癌(PC)的生长和增殖需要雄激素受体(AR)。我们将针对这种受体，就像目前市场上销售的抗雄激素药物一样。目前的药物都与AR的激素结合位点(HBS)结合，在那里它们改变了受体的动力学和结构，导致必要的辅助激活剂无法与辅助激活剂结合部位(AF-2)结合。最近已经确定了第三个位点--BF-3位点，它类似于激素位点，以变构方式影响AF-2位点上的辅活化子结合。(后者在变构上增强了共激活子的结合，而BF-3上的配体似乎是负对照)。我们将利用单个药物靶点中这种不同寻常的多个位点来执行基于片段的、多位点的药物发现策略，该策略利用实验和理论努力，并提供新的机械方法来克服先进的PC。为此，我们将与基于细胞的转录和增殖分析、X射线结晶学和分子动力学(MD)模拟相结合，以找到确认的HITS(X射线和分析)，并确定结构和动态设计标准，以在这些位置进行化合物的先导优化。 项目简介：这项工作的长期目标是开发新药，针对晚期前列腺癌的治疗，在治疗的几年内克服前列腺癌对现有药物产生耐药性的能力。因为，目前还没有治疗这种晚期疾病的有效药物，前列腺癌是男性癌症死亡的第二大原因。

DESCRIPTION (provided by applicant): The long-term goal of this work is to develop novel drugs, targeted to the treatment of advanced prostate cancer, which overcome the ability of all prostate cancers to evolve resistance to current antiandrogen drugs. These changes lead to a poor prognosis and represent a major clinical challenge to the successful treatment of advanced prostate cancer. Prostate cancer (PC) requires the androgen receptor (AR) for growth and proliferation. We will target this receptor as do current marketed antiandrogen drugs. Current drugs all bind to the hormone-binding site (HBS) of AR where they alter the dynamics and structure of the receptor, resulting in an inability of necessary coactivators to bind to the coactivator-binding site (AF-2). A third site has recently been identified -- the BF-3 site -- which, analogous to the hormone site, allosterically affects coactivator binding at the AF-2 site. (The latter allosterically enhances coactivator binding, while ligands at the BF-3 appear to be a negative control). We will exploit this unusual multiplicity of sites in a single drug target to carry out a fragment-based, multi-site, drug discovery strategy that leverages the experimental and theoretical efforts and provides new mechanistic approaches to overcoming advanced PC. To this end we will integrate in silico induced-fit docking with cell based transcription and proliferation assays, X-ray crystallography, and molecular dynamics (MD) simulations to find confirmed hits (X-ray and assays) and determine both structural and dynamic design criteria for lead optimization of compounds at these sites. Project Narrative: The long term goal of this work is to develop novel drugs, targeted to the treatment of advanced prostate cancer, that overcome the ability of prostate cancers to evolve resistance to current drugs within a few years of treatment. Because, there are currently no drugs effective against this advanced form of the disease, prostate cancer is the second leading cause of cancer deaths in men.