Inactivation of protein farnesyltransferase by active-site-targeted dicarbonyl compounds

Upon farnesylation by protein farnesyltransferase (FTase), key proteins bec ome compartmentalized in cells. For example, cell membrane localization is essential for the mitogenic role of mutant Ras protein, which acts as a swi tch for cancer cell proliferation. We repel? that alpha -dicarbonyl compoun ds derived from the isoprenoid skeleton or other hydrophobic groups potentl y obstruct farnesylation of a Ras model peptide by human recombinant FTase in vitro. A geranyl-derived isoprenoid diketone, 5.9-dimethyl-8-decene-2,3- dione, at 17 muM caused a 62% reduction in FTase activity after 30 minutes. A farnesyl-derived isoprenoid diketone, 5,9,13-trimethyl-8,12-tetradecadie ne-2,3-dione, at 93 muM caused a 94% reduction after 30 minutes. Other dica rbonyl:compounds found to be effective against FTase in vitro were (+/-)-6- (camphorquinone-10-sulfonamido)-hexanoic acid, 4,4 ' -biphenyldiglyoxaldehy de, dehydroascorbic acid 6-palmitace, 2-oxododecanal, and phenylglyoxal. Hi gher concentrations of the alpha -dicarbonyl compound resulted in more rapi d and more extensive inactivation. These findings demonstrate that ct-dicar bonyl compounds targeted to FTase interfere with protein farnesylation in v itro and may,lead to derivatives that have utility as chemotherapeutic agen ts.