Cancer is the second leading cause of death in the United States, contributing to one out of every four deaths. It is estimated that 555,500 people in the United States will die from cancer this year. Last year alone, cancer cost the United States' economy an amount of $156 billion in combined direct and indirect costs. This situation calls for the development of effective cancer therapies. The long-term goal of this research program is the discovery and preclinical development of compounds to target p53 pathway targets, specifically compounds that inhibit p53-Mdm2 interaction, using structure-based drug design and combinatorial chemistry in conjunction with mechanism-based assays. This grant proposal is designed to expand on biologically active lead compounds that were discovered through structure-based design using the reported X-ray crystallographic 3D atomic coordinates of the human p53 and Mdm2 binding complex. A series of compounds belonging to the beta-3-carboline class, that were among of lead compounds identified will be explore as potential novel molecularly target anticancer drugs, or as probes for cancer research. We have hypothesized that the observed effects of these compounds on elevation of cellular expression levels p53 and p21 stems from their inhibitory effect on p53-Mdm2 interaction.
The specific aims of this two-year R15 proposal are: 1) to test the hypothesis that this novel series of compounds exert their effect on p53 and p21 levels by inhibiting p53-Mdm2 interaction, and 2) to conduct structure-activity relationship (SAR) studies and generate combinatorial libraries for high throughput screening to optimize 13-carboline lead compounds as novel p53 potentiating agents. Traditional and combinatorial medicinal chemistry approaches, as well as 3D quantitative structure-activity relationship analyses will be employed together with p53-Mdm2 binding assays and high throughput antitumor assays to optimize lead compounds. This research program is planned to involve the participation of undergraduate students for the purpose of their training in biomedical research.
