The goals of this project are to further characterize the newly discovered Rcelp, a protease involved in the processing of Ras, and to identify inhibitors that may find utility as anti-cancer therapeutics. Studies in the yeast Saccharomyces cerevisiae have demonstrated that loss of Rcelp causes a quantitative decrease in Ras function. Rcelp will be characterized to determine how specific its role is with respect to Ras. These studies will include analyzing changes in global expression patterns in yeast in the presence and absence of Rcelp to reveal how many different processes are affected by loss of Rcelp function. We will determine what other substrates for Rcelp may exist in a cell and we will determine the residues critical for its catalytic activity. These studies will enable us to identify reporters that specifically change in response to loss of Rcelp function. In addition, a cell-based assay for high throughput screening to identify Rcelp- inhibitors from chemical libraries is currently being developed. PROPOSED COMMERCIAL APPLICATION Much research has gone into the development of Ras farnesyl transferase inhibitors--compounds that have shown some promise as an anti-cancer therapeutic. However, certain Ras alleles are geranylgeranylated in cells treated with farnesyl transferase inhibitors. These forms of Ras are still fully functional, thus limiting the therapeutic potential of farnesyl transferase inhibitors. Our research suggests that Rcelp will represent a viable target with which to inhibit Ras function that may be unaffected by the promiscuous nature of the prenylation of Ras. The validation of Rcelp as an anti-cancer target could lead to the development of an entirely new class of therapeutic agents with the potential to treat a broad range of human tumors.
