POTENT, CELL ACTIVE, NON-THIOL TETRAPEPTIDE INHIBITORS OF FARNESYLTRANSFERASE

All previously reported CAAX-based farnesyltransferase inhibitors cont ain a thiol functionality. We report that attachment of the 4-imidazol yl group, via 1-, 2-, or 3-carbon alkyl or alkanoyl spacers, to Val-Ti c-Met or tLeu-Tic-Gln provides potent FT inhibitors. yl-L-valyl]-3-iso quinolinyl]carbonyl]-L-methionine ([imidazol-4-yl-ethyl]-val-Tic-Met), with FT IC50 = 0.79 nM, displayed potent cell activity in the absence of prodrug formation (SAG EC(50) = 3.8 mu M).