Core - Drug, Discovery, Design and Synthesis

核心 - 药物、发现、设计和合成

基本信息

批准号：
8152937
负责人：
Gunda I. Georg
金额：
$ 112.45万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8152937
关键词：
Animals Arts Bioavailable Biological Biological Assay Biology Clinical Clinical Trials Collaborations Common Good Complex Computer Simulation Contraceptive Agents Core Facility Data Development Digit structure Drug Design Environment Future Goals Grant Hormonal In Vitro Institution Knowledge Laboratories Lead Libraries Male Contraceptions Male Contraceptive Agents Male Genital Organs Methods Molecular Chaperones Na(+)-K(+)-Exchanging ATPase National Institute of Child Health and Human Development Peptide Elongation Factor 1 Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Preparation Procedures Program Development Property Protein Tyrosine Kinase Proteins Recording of previous events Reproductive Biology Research Research Personnel Resolution Resource Development Screening procedure Solubility Spermatogenesis Structure Testing Therapeutic Universities Ursidae Family Vagina Work X-Ray Crystallography aqueous base cell motility combinatorial chemistry design drug development drug discovery fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether high throughput screening in vivo infancy inhibitor/antagonist innovation insight pre-clinical protein structure research clinical testing response small molecule sperm cell sperm protein transcription factor

项目摘要

3. Core Unit B: Drug Discovery, Design & Synthesis (Georg) a. Objective: The discovery and development of non-hormonal male contraceptive agents is in its infancy. However, knowledge about the basic biology of the male reproductive system has exploded and extensive biological insights provide the opportunity to initiate drug discovery and development programs. Contraceptive drugs must be highly effective, reversible, orally bioavailable or suitable for intra-vaginal application, and safe. In response to this opportunity and challenge we have assembled a core facility (Drug Discovery, Design & Synthesis Core, DDS) that will support this interdisciplinary U54 center with the expertise to discover, design, synthesize, and develop male contraceptive agents. In a highly collaborative manner with the PIs of this center, its drug development core, and the NICHD we will optimize hit and lead compounds for potency, selectivity, and pharmaceutical properties in preparation for clinical trails. The long-term goal of this center is the development of non-hormonal male contraceptive agents. For the current application we have selected several targets for drug discovery that are important for spermatogenesis, spermiation, motility and capacitation. The targets are the molecular chaperone Hsp90J3, eukaryotic elongation factor 1 a (eEF1A), Na,K-ATPase a4, Doublesex and Mab-3 related transcription factor-1 (Dmrt1), and sperm protein tyrosine kinases. In addition, it is anticipated that future junior investigators of the U54-center will work on other target proteins. The central research hypothesis for the core is that small molecule inhibitors of each of the targets can be discovered, optimized, and investigated in vitro and in vivo with the ultimate goal to bring one or more agents towards clinical trials. The investigators are well prepared to undertake this project because they have a track record of research in reproductive biology, drug discovery, drug' development, and a successful history of collaborating on the discovery and development of male contraceptive agents. The research environment for drug discovery is also excellent and provides unique facilities that are not often found at universities such as high throughput screening laboratories (KU), a combinatorial chemistry laboratory (UMN), a large-scale synthesis laboratory (UMN), an Office for Therapeutics Discovery and Development (KU), and a common Good Manufacturing Procedures (c-GMP) synthesis facility (UMN). Objective 1: Identify inhibitors for sperm-specific targets by high throughput screening and by screening of targeted libraries. In collaboration with the project PIs, we will develop assays that are suitable for high throughput screening. A compound library of over 100,000 compounds and/or smaller targeted libraries will be screened to identify small molecule inhibitors of the target proteins. Objective 2: Determine protein-inhibitor interactions by protein X-ray crystallography. The target proteins will be co-crystallized with lead compounds and the structure of the protein-hit complex(es) will be determined at atomic resolution. The structural data will be used for structure-based drug design to optimize hit compounds for potency and selectivity and for in silico screening. Objective 3: Optimize screening hits for potency and selectivity. Small molecules will be optimized for potency and selectivity, using structure-based drug design and other rational design medicinal chemistry principles. These studies will be carried out in close collaboration with the project PIs and the Drug Development Core. Compounds will be prepared, tested and then further optimized with the goal to generate single digit nanomolar inhibitors that posses about 1000-fold selectivity and aqueous solubility of >100 ¿mu¿g/ml. Objective 4: Develop lead compounds for preclinical and clinical evaluation. In collaboration with the Drug Development Core and the NICHD we will optimize the pharmaceutical properties of lead compounds in preparation for clinical trails. We will also provide large-scale amounts of lead compounds for animal studies. Our approach toward the discovery and development of non-hormonal male contraceptive agents is innovative because we have identified several highly promising targets that have not been explored for drug discovery before. We are bringing state-of-the-art drug discovery methods to bear on these projects and are looking forward to working with the other U54 centers and providing them with drug discovery and development resources and expertise that are rarely available at academic institutions. At the end of the five-year center grant we will have identified small molecule inhibitors for each of the targets, we will have co-crystallized small molecule inhibitors with the target proteins and will have used structural information about protein-inhibitor interactions for drug design. The screening hits will have been optimized for potency, selectivity, and pharmaceutical properties and we expect that at least one optimized lead compound will have been selected for clinical trials and will ultimately be commercialized for male contraception.

3. 核心单元B：药物发现、设计与合成（Georg）目标：非激素男性避孕药的发现和开发尚处于起步阶段，然而，有关男性生殖系统的基础生物学知识已经爆炸性增长，广泛的生物学见解为启动避孕药物必须高度重视的机会。有效、可逆、口服生物可利用或适合阴道内应用且安全。为了应对这一机遇和挑战，我们组建了一个核心设施（药物发现、设计和合成核心，DDS），该设施将为这个跨学科 U54 中心提供发现、设计、合成和开发男性避孕药的专业知识。通过与该中心的 PI、其药物开发核心和 NICHD 的合作，我们将优化命中化合物和先导化合物的效力、选择性和药物特性，为临床试验做准备。该中心的长期目标是开发非激素男性避孕药，对于当前的应用，我们选择了几个对精子发生、精子形成、运动和获能很重要的靶点。、真核延伸因子 1a (eEF1A)、Na,K-ATPase a4、Doublesex 和 Mab-3 相关转录因子 1 (Dmrt1)，以及此外，预计 U54 中心未来的初级研究人员将致力于其他靶蛋白的研究，核心研究假设是可以发现、优化每个靶点的小分子抑制剂。并进行体外和体内研究，最终目标是将一种或多种药物进行临床试验。研究人员为开展该项目做好了充分准备，因为他们在生殖生物学、药物发现、药物开发方面拥有良好的研究记录，并且在男性避孕药的发现和开发方面拥有成功的合作历史。药物发现的研究环境。也非常出色，提供大学中不常见的独特设施，例如高通量筛选实验室 (KU)、组合化学实验室 (UMN)、大规模合成实验室 (UMN)、治疗药物发现和开发办公室(KU) 和通用良好生产程序 (c-GMP) 合成设施 (UMN)。目标 1：通过高通量筛选和目标库筛选，我们将开发适合高通量筛选的检测方法包含超过 100,000 种化合物和/或化合物的库。将筛选较小的目标文库以鉴定目标蛋白的小分子抑制剂。目标 2：通过蛋白质 X 射线晶体学确定蛋白质-抑制剂相互作用。目标蛋白质将与先导化合物共结晶，并以原子分辨率确定蛋白质复合物的结构。用于基于结构的药物设计，以优化命中化合物的效力和选择性以及计算机筛选。目标 3：优化筛选命中的效力和选择性。将利用基于结构的药物设计和其他合理设计药物化学原理，优化小分子的效力和选择性。这些研究将与项目 PI 和项目负责人密切合作进行。药物开发核心。化合物将被制备、测试，然后进一步优化，目标是产生具有约 1000 倍选择性和 >100 水溶性的单位数纳摩尔抑制剂。 ¿亩克/毫升。目标 4：开发用于临床前和临床评估的先导化合物，我们将与药物开发核心和 NICHD 合作，优化先导化合物的药物特性，为临床试验做好准备。我们还将为动物提供大量先导化合物。研究。我们发现和开发非激素男性避孕药的方法是创新的，因为我们已经确定了几个以前从未探索过的药物发现的非常有前途的目标，我们正在将最先进的药物发现方法付诸实践。这些项目，并期待与其他 U54 中心合作，为他们提供学术机构很少提供的药物发现和开发资源和专业知识。在五年中心拨款结束时，我们将确定每个目标的小分子抑制剂，我们将与目标蛋白质共结晶小分子抑制剂，并将使用有关蛋白质-抑制剂相互作用的结构信息进行药物设计筛选的化合物将针对效力、选择性和药物特性进行优化，我们预计至少一种优化的先导化合物将被选择用于临床试验，并最终将用于男性避孕。