Protein farnesyltransferase inhibitors block the growth of ras-dependent tumors in nude mice.
The posttranslational addition of a farnesyl moiety to the Ras oncoprotein is essential for its transforming activity. Cell-active inhibitors of the enzyme that catalyzes this reaction, protein farnesyltransferase, have been shown to selectively block ras-dependent transformation of cells in culture. Here we describe the protein farnesyltransferase inhibitor 2(S)-[2(S)-[2(R)-amino-3-mercapto]propylamino-3(S)-methyl] pentyloxy-3-phenylpropionylmethioninesulfone methyl ester (L-739,749), which suppressed the anchorage-independent growth of Rat1 cells transformed with viral H-ras and the human pancreatic adenocarcinoma cell line PSN-1, which harbors altered K-ras, myc, and p53 genes. This compound also suppressed the growth of tumors arising from ras-transformed Rat1 cells in nude mice by 66%. Under the same conditions, doxorubicin inhibited tumor growth by 33%. Control tumors formed by v-raf- or v-mos-transformed Rat1 cells were unaffected by L-739,749. Furthermore, mice treated with L-739,749 exhibited no evidence of systemic toxicity. This is a demonstration of antitumor activity in vivo using a synthetic small molecule inhibitor of protein farnesyltransferase.
Kohl
N E
NE
Department of Cancer Research, Merck Research Laboratories, West Point, PA 19486.
Wilson
F R
FR
Mosser
S D
SD
Giuliani
E
E
deSolms
S J
SJ
Conner
M W
MW
Anthony
N J
NJ
Holtz
W J
WJ
Gomez
R P
RP
Lee
T J
TJ
D019883:Alkyl and Aryl Transferases; D000818:Animals; D002472:Cell Transformation, Viral; D016258:Genes, mos; D011905:Genes, ras; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000494:pharmacology*; D014166:Transferases / Q000037:antagonists & inhibitors*
C089417:L 739750; D009842:Oligopeptides; C087363:L 739749; D014166:Transferases; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase