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Báo cáo khoa học: PLENARY LECTURES DATTA LECTURE

Small molecules that activate the transcriptional function of wild type p53 have proved active as anti-cancer drugs in preclinical models and are now entering clinical trial. The complexity of the upstream p53 signaling pathway offers many targets for the devel-opment of such activators and the action of Mdm2 inhibitors, kinase inhibitors, sirtuin inhibitors and low doses of actinomycin D will be described among other examples. | Plenary Lectures Abstracts PLENARY LECTURES DATTA LECTURE PL 1 Drug discovery in the p53 pathway D. Lane Division of Molecular Medicince College of Life Sciences Medical Sciences Institute Edinburgh UK Small molecules that activate the transcriptional function of wild type p53 have proved active as anti-cancer drugs in preclinical models and are now entering clinical trial. The complexity of the upstream p53 signaling pathway offers many targets for the development of such activators and the action of Mdm2 inhibitors kinase inhibitors sirtuin inhibitors and low doses of actinomycin D will be described among other examples. The possibility of using combinations of molecules will also be analyzed as will the issues of toxicity and resistance expected from these types of molecules. One concern is that the activation of p53 might exert some specific harmful affect on normal tissues and another is that treatment with p53 activators will select for tumor cells in the population that have mutant p53. What can be done in those cases where p53 is mutant One approach is the search for molecules that re-activate mutant p53 proteins though some have likened this to trying to unscramble eggs recent discoveries in protein dynamic and protein folding pathways have been very exciting. Recent approaches to developing molecules that will chaperone mutant p53 s to fold in the active state will be described with reference to recent crystallographic analysis. A second conceptual approach to exploiting the frequent loss of p53 function in tumors is that of synthetic lethality. Might p53 mutant tumors be more susceptible to inhibitors of DNA repair as has been seen for BRCA1 mutant tumors for example Finally the concept of using p53 activating molecules as chemo-protectives has been proposed. In this concept normal cells are arrested temporarily in GI by p53 activators such as the Mdm2 inhibitor Nutlin. These cells are thus protected from cytotoxic drugs active at G2 M such as taxol. .