The goal of the proposed research is to develop a potent, pharmacologically useful inhibitor of farnesyltransferase for use as a new therapeutic agent for cancer. The Ras family of oncogenes and proto-oncogenes encode guanine nucleotide binding proteins that participate in the control of eukaryotic cell proliferation. Ras proteins are modified posttranslationally by transfer of a farnesyl moiety to specific cysteine residues. This transformation is mediated by a farnesyl:protein transferase (farnesyltransferase). Farnesylation is a prerequisite for oncogenic transformation. There is a convincing body of evidence indicating that inhibition of Ras farnesylation is an important point for pharmacological intervention in Ras function. In this proposal we will: 1) Design and synthesize novel inhibitors of farnesyltransferase; 2) Evaluate the new compounds as inhibitors of farnesyltransferase in an in vitro assay. The compounds developed in these studies will greatly increase our knowledge of the structure-activity relationships for farnesyltransferase inhibitors and may lead to the development of new cancer therapeutics.
