Novel farnesol and geranylgeraniol analogues: A potential new class of anticancer agents directed against protein prenylation

Protein farnesyltransferase (FTase), the enzyme responsible for protein far nesylation, has become a key target for the rational design of cancer chemo therapeutic agents. Herein it is shown that certain novel prenyl diphosphat e analogues are potent inhibitors of mammalian FTase. Furthermore, the alco hol precursors of two of these compounds are able to block anchorage-indepe ndent growth of ras-transformed cells. While 3-allylfarnesol inhibits prote in farnesylation, 3-vinylfarnesol instead leads to abnormal prenylation of proteins with the 3-vinylfarnesyl group. In a similar manner, 3-allylgerany lgeraniol acts as a highly specific inhibitor of protein geranylgeranylatio n, while 3-vinylgeranylgeraniol restores protein geranylgeranylation in cel ls. This study indicates that certain prenyl alcohol analogues can act as p renyltransferase inhibitors in situ, via a novel prodrug mechanism. These a nalogues may prove to be valuable tools for investigating the therapeutic c onsequences of inhibiting geranylgeranylation relative to farnesylation. Fu rthermore, the 3-vinyl alcohol analogues can inhibit transformed cell growt h through a mechanism not involving prenyltransferase inhibition.