Selective inhibition of farnesyl-protein transferase blocks ras processing in vivo.
The ras oncogene product, Ras, is synthesized in vivo as a precursor protein that requires post-translational processing to become biologically active and to be capable of transforming mammalian cells. Farnesylation appears to be a critical modification of Ras, and thus inhibitors of the farnesyl-protein transferase (FPTase) that catalyzes this reaction may block ras-dependent tumorigenesis. Three structural classes of FPTase inhibitors were identified: (alpha-hydroxyfarnesyl)phosphonic acid, chaetomellic acids, and zaragozic acids. By comparison, these compounds were weaker inhibitors of geranylgeranyl-protein transferases. Each of these inhibitors was competitive with respect to farnesyl diphosphate in the FPTase reaction. All compounds were assayed for inhibition of Ras processing in Ha-ras-transformed NIH3T3 fibroblasts. Ras processing was inhibited by 1 microM (alpha-hydroxyfarnesyl)phosphonic acid. Neither chaetomellic acid nor zaragozic acid were active in this assay. These results are the first demonstration that a small organic chemical selected for inhibition of FPTase can inhibit Ras processing in vivo.
Gibbs
J B
JB
Department of Cancer Research, Merck Research Laboratories, West Point, Pennsylvania 19486.
Pompliano
D L
DL
Mosser
S D
SD
Rands
E
E
Lingham
R B
RB
Singh
S B
SB
Scolnick
E M
EM
Kohl
N E
NE
Oliff
A
A
D016475:3T3 Cells; D019883:Alkyl and Aryl Transferases; D000818:Animals; D001921:Brain / Q000201:enzymology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002417:Cattle; D002461:Cell Line, Transformed; D005204:Farnesol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D011905:Genes, ras; D007700:Kinetics; D008298:Maleates / Q000494:pharmacology*; D051379:Mice; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D014166:Transferases / Q000037:antagonists & inhibitors* / Q000235:genetics; D014233:Tricarboxylic Acids / Q000494:pharmacology*
C080570:(alpha-hydroxyfarnesyl)phosphonic acid; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D008298:Maleates; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D014233:Tricarboxylic Acids; C075117:squalestatin 1; C080569:chaetomellic acid A; D005204:Farnesol; D014166:Transferases; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C064911:p21(ras) farnesyl-protein transferase