) For the five-year period of requested support, we propose to discover and develop novel anticancer agents derived from natural product sources, using the specific approaches shown below. 1. Acquire and screen a diverse range of natural product extracts from several sources to allow for efficient drug discovery, with approximately 9000 extracts/year from the Council for Scientific and Industrial Research (CSIR) in South Africa and approximately 300 extracts/year from the Institute for Crop and Food Research (CFR) of New Zealand, both countries with a high rate of endemism and biodiversity """"""""hotspots"""""""" 2. Discover new bioactive natural product extracts with mechanisms of action that are known to be therapeutically important by mining the National Cancer Institute's (NCI) Division of Therapeutics in-house database and by using selective yeast bioassays by using the COMPARE algorithm to identify extracts in the NCI repository that have the same mechanism of action as topotecan, a known topoisomerase I inhibitor, or etoposide, a clinically important topoisomerase II inhibitor. Activity will be confirmed by the use of yeast-based assays to confirm topoisomerase I and II inhibitors. 3. Collaborate with SmithKline Beecham to discover additional topoisomerase I and II inhibitors and additional DNA-damaging agents by screening all available extract banks with a selective yeast bioassay. 4. Discover new bioactive natural products with novel mechanisms of action against a range of new targets using bioasssays newly developed at SmithKline Beecham Pharmaceuticals. Targets of interest include Myt1 kinase, checkpoint kinases 1 and 2, polo-like kinase, protein kinase B, tie2 receptor tyrosine kinase, vas protease, and histone deacetylases 3 and 4. 5. Carry out drug discovery on active extracts by fractionation of the confirmed active extracts against the appropriate bioassay and isolation and structure elucidation of the isolated active compounds, 6. Characterize the mode of action of the isolated active compounds in collaboration with SmithKline Beecham and the University of Virginia. 7. Obtain adequate quantities of agents identified above for in vivo testing in animal tumor models. 8. Provide extracts from the South African and New Zealand collections to Program 3 for fractionation when there is insufficient capacity in Associate Program 2.
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