STRUCTURAL STUDIES ON NATURAL PRODUCT LEADS FOR RESTORATION OF P53 FUNCTION

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The goal of the NCNPDD group is to target the p53 tumor suppressor system int he screening of natural compound libraries in an attempt to identify compounds that restore the activity of p53 in tumor cells. Recent rapid advances in cancer research have identified the p53 tumor suppressor system as the body-s forefront defense against cancer. p53 is the most frequently mutated gene identified in human cancers. Mutations occur in over 50 percent of all cancer cases, and many of the remaining cases involve cellular or viral oncogenes that inactivate the p53 protein. The cellular and biochemical mechanisms mediating p53's tumor suppressing effects have recently been elucidated. At the cell biological level, p53 can induce cell cycle arrest and programmed cell death in response to DNA damage or inappropriate growth signals. At the biochemical level, p53 can bind to specific DNA sequences and activate the transcription of genes. Tumor derived p53 mutants are defective in DNA binding, and consequently they cannot induce cell cycle arrest or apoptosis. In addition to the cellular and biochemical mechanisms, the recent determination of the crystal structure of a p53-DNA complex by this laboratory has also elucidated the structural basis of p53 function. To further address issues pertaining to p53's inactivation by mutations in tumors, systematic biochemical, biophysical, and crystallographic studies of a large set of tumor derived p53 mutants will be undertaken as part of this laboratory program. The mechanism based differences between wild type and mutant p53, and in particular biochemical and structural differences, will be explored in the rational design of natural product screens in attempt to identify compounds that restore function to tumor derived p53 mutants. Lead compounds emerging from the screens will be co-crystallized in order to determine their mechanism of action, and to aid in their development into useful therapeutic agents. Structural studies will be extended to (i) the MDM2 oncogene which is p53's natural inhibitor and has been found amplified in certain tumors, and (ii) the Cip1/WAF1-cyclin-cdk complex which appears to mediate p53's growth inhibitory effects. Emphasis will be on determining their structural mechanisms of action of MDM2 and of Cip1/WAF1 to aid in the rational design of model systems to be used in the screening efforts. Lead compounds emerging from the screens will be co-crystallized in complex with their target proteins to facilitate their development into useful therapeutic agents.