Local constrained shifty pseudopeptides inhibitors of rasfarnesyl transferase

Pseudopeptide analogues related to the C-terminal tetrapeptide of ras-protein (Cys-Val-X-Met) were synthesized and evaluated for inhibition of ras farnesyl transferase (FTase). We demonstrate that the introduction of a shifty amino acid related to Cys instead of Cys-Val and a tetrahydroisoquinoline carboxylic acid (TIC) instead of Phe lead to potent inhibitors of FTase on isolated enzyme or on cell based tests. One of the pseudopeptides, conceived as a prodrug, suppressed specifically the ability of ras transformed cells to form colonies in soft agar.