A novel series of stable analogs of geranylgeranyl diphosphate (GGdP) are described in which the biologically labile diphosphate moiety of GGdP is replaced by portions that can act as stable isosters. The compounds inhibited the geranylgeranyltransferase activity in whole PC-3 prostate cancer cells, as determined by the inhibition of post-translational isoprenylation of the small GTP-binding protein p21rap 1 and the accumulation of unprocessed p21rap 1 in the cytosolic fraction. However, the compounds did not affect the farnesylation of p21ras, as shown by protein immunoprecipitation after whole cell labeling with [3 H]-(R,S)-mevalonolactone. Despite the absence of effects of post-translational processing of p21ras, these compounds proved to be cytotoxic for prostate cancer cells, with half-maximal inhibition of cell growth obtained in the range 18.5-35.1 microM. The GGdP analogs described in the this study are novel, non-peptidic inhibitors of geranylgeranylation that may be active as antitumor agents.