Synthesis and biological activity of semipeptoid farnesyltransferase inhibitors

Semipeptoids derived from the Ras farnesyl transferase inhibitor, CVFM, were synthesized by the Simultaneous Multiple Analogue Peptide Synthesis methodology. The semipeptoids were screened for their in vitro inhibition potency towards farnesyl transferase and geranylgeranyl transferase. Structure-activity relationship studies led to a potent and selective inhibitor, HR-11, which blocks Ras farnesylation in vitro with an IC₅₀ of 1.2 nM. The cell permeable methyl ester derivative of HR-11, HR-12, inhibits Ras farnesylation in intact cells with an IC₅₀ of 10 μM and with no detectable inhibition of Rap1A/K-rev geranyl-geranylation.