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, DOS) 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 Hsp90p, eukaryotic elongation factor 1oc (eEF1A), Na,K-ATPase a4, Doublesex and Mab-3 related transcription factor-1 (Dmrtl), 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 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.
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