NEW STRATEGIES FOR DRUG DISCOVERY AND DEVELOPMENT

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This research group's central aims are (1) to develop new analytical and experimental strategies for drug discovery in cancer and AIDS, and (2) to apply those strategies to biologically and therapeutically important problems. Analytical results: l. Neural networks able to predict mechanism of drug action on the basis of patterns of activity in DTP's 60-cell line cancer drug screen. 2. A program package (DISCOVERY) that integrates information on the chemical structure, activity, and molecular targets of compounds tested by NCI. As the name suggests, DISCOVERY was designed to search for novel mechanisms of action among the 48,000 compounds tested to date. 3. Identification of candidate cell lines for replacement in the screen by breast, prostate, target-selected, and target-transfected lines. 4. Preliminary neural nets and statistical methods to predict clinical activity of phase II-evaluable drugs on the basis of patterns of activity in the screen. 5. Use of DISCOVERY to identify what we term "p53-inverse" agents, i.e., compound that appear more active in p53-mutant than in p53-wild type cell lines. 6. QSAR studies and pharmacophore searches in the NCI's DIS database to identify new inhibitors of HIV- l integrase. 7. Use of "information intensive" strategies to create an information interface between the cancer and AIDS drug discovery programs. With respect to experimental studies we are: 1. Characterizing mRNA and protein "targets" in cell of the NCI cancer and AIDS screens. A major aspect is 2-D gel electrophoresis to develop a large-scale resource database on hundreds of proteins in the cells. 2. Developing a mass spectrometry method to identify proteins in the 2-D gels. 3. Completing development of a hollow fiber model of solid tumors and an angiogenesis model, both for use in in vitro testing of new therapies.