N-ARYLALKYL PSEUDOPEPTIDE INHIBITORS OF FARNESYLTRANSFERASE

Inhibitors of Ras protein farnesyltransferase are described which are reduced pseudopeptides related to the C-terminal tetrapeptide of the R as protein that signals farnesylation. Reduction of the carbonyl group s linking the first three residues of the tetrapeptide leads to active inhibitors which are chemically unstable. Stability can he restored b y alkylating the central amine of the tetrapeptide. Studies of the SAR of these alkylated pseudopeptides with concomitant modification of th e side chain of the third residue led to ylmethylamino}acetylamino)-4- methylsulfanylbutyric acid (11), a subnanomolar inhibitor. The methyl ester (10) of this compound exhibited submicromolar activity in the pr ocessing assay and selectively inhibited anchorage-independent growth of Rat1 cells transformed by v-ras at 2.5-5 mu M.