Novel farnesol and geranylgeraniol analogues: A potential new class of anticancer agents directed against protein prenylation.
Protein farnesyltransferase (FTase), the enzyme responsible for protein farnesylation, has become a key target for the rational design of cancer chemotherapeutic agents. Herein it is shown that certain novel prenyl diphosphate analogues are potent inhibitors of mammalian FTase. Furthermore, the alcohol precursors of two of these compounds are able to block anchorage-independent growth of ras-transformed cells. While 3-allylfarnesol inhibits protein farnesylation, 3-vinylfarnesol instead leads to abnormal prenylation of proteins with the 3-vinylfarnesyl group. In a similar manner, 3-allylgeranylgeraniol acts as a highly specific inhibitor of protein geranylgeranylation, while 3-vinylgeranylgeraniol restores protein geranylgeranylation in cells. This study indicates that certain prenyl alcohol analogues can act as prenyltransferase inhibitors in situ, via a novel prodrug mechanism. These analogues may prove to be valuable tools for investigating the therapeutic consequences of inhibiting geranylgeranylation relative to farnesylation. Furthermore, the 3-vinyl alcohol analogues can inhibit transformed cell growth through a mechanism not involving prenyltransferase inhibition.
Gibbs
B S
BS
Department of Cell Biology, Parke-Davis Pharmaceutical Research, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA.
Zahn
T J
TJ
Mu
Y
Y
Sebolt-Leopold
J S
JS
Gibbs
R A
RA
D019883:Alkyl and Aryl Transferases / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002384:Catalysis; D004224:Diterpenes / Q000737:chemistry*; D004591:Electrophoresis, Polyacrylamide Gel; D005204:Farnesol / Q000031:analogs & derivatives*; D007700:Kinetics; D008956:Models, Chemical; D017368:Protein Prenylation / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004224:Diterpenes; D005204:Farnesol; C017338:geranylgeraniol; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase