PEPTIDOMIMETIC INHIBITORS OF RAS FARNESYLATION AND FUNCTION IN WHOLE CELLS

The ras protooncogene is involved in regulation of cell growth. Mutati ons that activate the protein result in uncontrolled cell growth. Ras undergoes a series of post-translational processing events, the first of which, farnesylation, is crucial for the function of the protein. I nhibitors of the farnesyltransferase enzyme are therefore potential ca ndidates for the development of anticancer drugs. Tetrapeptides have b een reported to be good inhibitors of this enzyme in vitro. We have sy nthesized analogs of the tetrapeptide Cys-Val-Phe-Met by replacement o f the amino-terminal amide bonds. One inhibitor, B581, is permeable to the cell membrane. In the cell, it inhibits processing of two farnesy lated proteins, H-ras and lamin A, but it does not inhibit processing of a geranylgeranylated protein, Rap 1A. Microinjection of B581 into f rog oocytes inhibits maturation induced by activated, farnesylated H-r as but not maturation induced by activated, geranylgeranylated H-ras o r by progesterone. These results demonstrate that this peptide mimic i nhibits farnesylation selectively in the cell. The inhibition of farne sylation results in inhibition of H-ras function.