Transformation by Ras oncogene proteins requires their modification (prenylation) by a farnesyl isoprenoid lipid. Therefore, specific inhibitors of the farnesyl transferase (FTase) enzyme responsible for this modification may represent novel anti-cancer chemotherapeutic agents. The overall goal of this Program (#3) will be to establish the biochemical basis for the ability of FTase inhibitors to inhibit both Ras transformation and the Ras signal transduction pathways that are responsible for this transformation. This proposal represents a logical extension of our previous studies on protein prenylation, Ras signal transduction and oncogene transformation. Recent studies with FTase inhibitors by ourselves and others have suggested that normal cells are insensitive to the inhibitory activity of such compounds and that the observed reversal of Ras transformation may be due to a more complex mechanism than simply to antagonizing oncogenic Ras function. Therefore, it is clear that the specific biochemical and biological consequences of FTase inhibitor action remain to be determined. We propose six specific aims to accomplish three primary goals. First, we will test FTase inhibitors (developed by Program #1 and initially characterized by Program #2) for their ability to specifically and efficaciously antagonize Ras signal transduction and transformation (Specific Aims 1, 2 and 3). Second, we will determine if other prenylated proteins are also perturbed by treatment with FTase inhibitors (Specific #4). These studies will emphasize the analysis of Ras-related proteins that influence cell growth. Third, we will utilize these inhibitors to address the role of Ras in specific cellular processes (e.g., differentiation, radioresistance) (Specific Aims 5 and 6). Because of the complex and distinct roles that Ras plays in different systems (growth, differentiation, apoptosis), understanding the consequences of FTase inhibition in the intact animal will require the study of diverse cell types. Candidate FTase inhibitors that perform well in these assays will be tested in an animal model system by Program #2. Feedback provided by us to Programs #1 and #2 at each step of the process will enable the design and synthesis of improved candidates for testing. Thus, while our primary goal will be to complement the studies in Programs #1 and #2 to achieve FTase inhibitors that will be clinically useful in human cancers, our studies are designed to accomplish this goal by providing a better understanding of the role and mechanism of prenylation in protein function and of the role of Ras in normal cell function.
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