) The goal of this new NCDDG proposal """"""""Anticancer drugs active against cell cycle and signal pathways targets is to discover effective new agents acting against novel, validated cell cycle, signaling pathways and apoptosis targets for the treatment of cancer and to bring the resulting agents to the stage of preclinical testing to clinical trials. The overall hypothesis is that mechanistically driven drug screening employing defined molecular targets critical to the development and progression of cancer will provide novel and effective agents for the treatment of human cancer. The NCDDG is a contemporary, mechanistically-based and integrated cancer drug discovery and development effort employing state-of-the art technology from several different fields. The NCDDG objectives are: 1) to identify a series of novel cancer-related signaling and cell cycle targets and to obtain molecular proof-of-principle that their inhibition leads to reversal of the cancer cell phenotype; 2) to develop automated high capacity biochemical or cell based assays, including cell based fluorescence biosensor assays, to study and to identify inhibitors of the targets; 3) to screen a library of diverse chemical structures to identify' lead compounds as inhibitors of the targets; 4) to use advanced combinatorial chemistry and parallel synthesis to optimize lead compounds with improved potency and selectivity; 5) to use DNA microarray as a guide to improving the selectivity of analogues; and, 6) to conduct preclinical development studies including tumor cell and animal antitumor testing, pharmacology and preliminary toxicology on the most active compounds. The unique characteristics of the NCDDG are: a) its multidisciplinary nature b) novel targets that have been validated using contemporary molecular and cell biology approaches; c) several cutting edge technologies for drug discovery., including state-of-the art automated high throughput screening. DNA microarray technology, cell based fluorescent biosensor assays, and combinatorial chemistry and parallel synthesis; d) rational contemporary approaches to the preclinical development of lead compounds; e) a cadre of investigators who are recognized experts in their respective fields with a track record of working together. and f)a commercial partner that is a successful new biotechnology cancer drug development company
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