The recent advances in our understanding of the role of aberrant signal transduction in the development of cancer provide an exciting opportunity for the discovery and development of new anti-tumor drugs. One of the few constriction points though which much cellular information flows is protein kinase C (PKC). The central position of this enzyme in cellular signal transduction as it is presently understood and the evidence from experiments with currently available activators and inhibitors of PKC indicate that modulation of PKC is a reasonable target for drug development. This project will take advantage of well established methods for the assay of modulation of PKC and the high affinity and novelty resulting from the structural complexity often associated with natural products, to discover and isolate natural products that modulate PKC. A better understanding of the basis of the biological and biochemical outcome of modulation of PKC will be useful for determining the feasibility and improving the efficiency of further drug discovery and development. To gain such understanding, it is necessary to investigate the structure-activity relationship of modulating agents both by semi-synthesis of novel and known modulatory agents and by correlation of the biochemical mechanism and selectivity of action with the biological efficacy. The latter will be determined by testing cytotoxicity of human tumor cell lines in vitro and in the nude mouse xenograft assay. While no single approach to drug discovery is guaranteed to be successful, this proposal has attempted to maximize the chances of success by carefully planning the approach cognizant of the information currently available and by keeping the approach flexible to take advantage of new information about the role of PKC in signal transduction and the role of signal transduction in the development and maintenance of the cancer cell phenotype.
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