) Telomerase represent perhaps the most exciting, universal, and specific molecular target in cancer. The proposed NCDDG will exploit this unique opportunity by discovering and developing new chemical entities that will inhibit telomerase activity in malignant cells. A common characteristic of tumor cells is their capacity for unlimited replication, or cellular immortality. The expression of the ribonucleo protein enzyme telomerase is necessary for cell immortality. In contrast to most oncolytic drugs that have limited selectivity and therefore significant toxicity, telomerase inhibitors should exhibit a large therapeutic index since cancer cells do express telomerase and most normal cells do not. A telomerase drug discovery program has been established to identify and develop new chemical entities that inhibit telomerase. Compounds will initially be tested in a high through-put cell-free assay. Active compounds will be profiled in secondary assays to establish their mechanism of action and specificity. Successive iterations of chemical modifications followed by compound evaluation in the secondary assays will be used to improve the potency and specific type of promising compounds(s). When sufficient potency and specificity are achieved, the lead com-pounds will be tested in ex vivo and in vivo tumor models. Based on the results of these studies, a candidate compound will be selected for preclinical development in anticipation of filing an IND.
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