The major objective of this proposed research program is to develop new types of anticancer agents by preparing a new kind of enzyme inhibitor that will inhibit enzymes on the de novo pathways to nucleotides and nucleic acids. Thymidine kinase, nucleoside diphosphate reductase and inosinic acid dehydrogenase are the enzymes selected for study. Success with any of these enzymes will allow extension to other enzymes critical to cell proliferation. The design of the potential inhibitors is based on the precise knowledge, from X-ray crystallography, of the binding of nucleotides to the enzyme active site, as exemplified by the binding of calcium-thymidine 3', 5'-diphosphate to nuclease. Potential inhibitors, and intermediates, will be studied at three levels: the isolated enzyme, whole cells in culture, and in vivo experimental animal tumor systems. Information gained from these systems, as well as from chemical studies with these compounds, will guide the synthesis program.