) The goal of the proposed research is to use mechanism-based screens to identify natural products with unique structure and/or mechanism of action for the treatment of cancer. To achieve this objective, the following specific aims are defined: 1. Screen approximately 1500 marine invertebrate, fungi, and micro- organism samples per year provided by the NCDDG and our internal Natural Products Group. The mechanistic- based screens include 6 receptor- tyrosine kinase enzymatic assays, 1 cytoplasmic tyrosine kinase enzymatic assay, 4 serine/threonine kinase enzymatic assays, 2 assays to identify transcriptional inhibitors, 2 assays to identify compounds that selectively target cell-cycle check-point, and a selective protease inhibitor assay. 2. Provide biologic support for the bioassay-guided purification of active extracts. This will be accomplished by evaluating the activity of fractionated entities in either the screening assay, or in secondary (i.e. cell-based) assays. 3. Evaluate the activity of purified active molecules in secondary, cell and biochemical-based, assays. 4. Use medicinal chemistry to define the structure-activity relationship of active molecules. Chemical efforts will be used where successful synthesis of the natural product or active analog can be achieved. 5. Perform in vivo evaluation of compounds with activity in primary and secondary screen. In vivo evaluation will consist of inhibition of the growth of human tumors in nude mice and where possible, pharmacokinetic studies to determine if effective blood-levels of the active molecule can be achieved in animals. Surrogate markers for activity (e.g. inhibition of RTK phosphorylation in tumors) will be attempted to further demonstrate mechanism-based action of candidate molecules. 6. Design and implement preclinical and clinical strategies for the development of lead compounds.
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