Design and synthesis of novel Ras farnesyl protein transferase inhibitors

CHED 295

Kerrie E. Walters and Mark F. Mechelke, mfmechelke@stcloudstate.edu. Department of Chemistry, St. Cloud State University, 358 Wick Science Building, 720 Fourth Avenue South, St. Cloud, MN 56301
Ras proteins play an important role in the signal transduction pathways that regulate cell proliferation. In order to perform their function, Ras proteins must first become post-translationally modified. The key step in this process is the addition of a fifteen carbon farnesyl tail to the Ras protein, catalyzed by the enzyme farnesyl protein transferase. The Ras farnesylation process has been a target for the hindrance of cancer, since mutated Ras proteins are associated with approximately 25% of human malignancies. Mutant Ras proteins that cannot be farnesylated do not stimulate malignant growth. This research focuses on the synthesis of competitive farnesyl protein transferase inhibitors. The compounds being prepared incorporate two aromatic rings in the farnesyl tail. It is anticipated that these farnesyl pyrophosphate mimetics will bind tighter to the enzyme active site, therefore blocking Ras farnesylation.