The long-term goal of this project continues to be the development of new agents for the treatment of human cancers. Most nucleosides require activation to the monophosphate level by one or more cellular kinases, followed by further activation to the triphosphate level prior to exerting their cytotoxic effects. We propose to continue our focused program of obtaining new structure-activity relationship (SAR) information on these key enzymes as we pursue new anticancer agents. Our initial targets are a series of nucleosides, both purine and pyrimidine, that have variously altered carbohydrate moieties. Building on knowledge derived from our laboratory and others, our first targets will include mainly new 4'-substituted nucleosides. A series of 3'-ethynyl- substituted nucleosides are also proposed as initial targets. Newly synthesized nucleosides will be evaluated in vitro in Project 3 and in Core B for their cytotoxic effects. In parallel, compounds will be sent to the laboratories of our collaborators, Drs. Staffan Eriksson and Donna Shewach, to determine their behavior with the cellular kinases that are responsible for initial metabolism of nucleosides. Compounds that exhibit significant cytotoxicity in our cell lines will then be examined for their anticancer activity in animal model systems in Core B. Any compounds that have anticancer activity in vivo, or that have other properties of particular interest, will be evaluated for their mechanism of action in Project 3. Our data as well as that supplied from Drs. Eriksson and Shewach will be utilized as described by the drug design and development flow chart included herein. Larger quantities of intermediates or final products that are needed for biological evaluations, as well as any triphosphates of inactive nucleosides, will be prepared through Core A. Depending upon the results from these compounds, we will focus on certain directions, or expand our targets based upon SAR to date. A key addition to this project is structural biology. Dr. Steven Ealick formally joins the project with an initial goal of obtaining structures for complexes of deoxycytidine kinase with phosphate donors and substrate/ inhibitors. As we obtain active site information, we will be able to apply all of that information to the design of new molecules, or to the modification of existing ones.
Showing the most recent 10 out of 80 publications
