) Cell cycle checkpoints ensure that critical cell cycle events, including commitment to enter S phase, and entryinto M phase, occur only in cells that have properly and accurately executed critical preliminary events. The consequences of cell-cycle checkpoint dysfunction are uncontrolled growth, genomic instability , and cancer development. An important checkpoint for normal cell growth is the restriction point, which occurs in mid/late G1-phase of the cell cycle. Recent results suggest that mTOR, the protein targeted by the antiproliferative drug, rapamycin, plays a key role driving G1 progression in certain cancer cells. In addition, it has become clear that p53-deficient tumor cells express an abnormal, DNA-damage activated checkpoint that protects these cells from entering a catastrophic mitosis. The hypothesis upon which Project #1 is based is that checkpoint defects represent a universal abnormality of human cancer cells, and therefore provide a rich source of targets for the development of novel anticancer agents. The major objectives of this project are (1)to implement a screen for novel inhibitors of mTOR kinase activity, and (2) to develop a cell-based screen for inhibitors of the abnormal G 2 checkpoint in p53-deficient tumor cells. These screens will be used to identify novel compounds from a large, chemically diverse library , and for lead optimization through the use of combinatorial chemistry, and collaborative interactions with other components of the NCDDG. A series of secondary assays and engineered cellular models will be used to assess the selectivity and activities of hits from the primary screens. The overarching goal of this project is to move, through the NCDDG, novel drugs for preclinical testing as anticancer agents.
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