LOCAL CONSTRAINED SHIFTY PSEUDOPEPTIDES INHIBITORS OF RAS-FARNESYL 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 introduct ion of a shifty amino acid related to Cys instead of Cys-Val and a tet rahydroisoquinoline carboxylic acid (TIC) instead of Phe lead to poten t inhibitors of FTase on isolated enzyme or on cell based tests. One o f the pseudopeptides, conceived as a prodrug, suppressed specifically the ability of ras transformed cells to form colonies in soft agar.