Selective inhibition of ras-dependent transformation by a farnesyltransferase inhibitor.
To acquire transforming potential, the precursor of the Ras oncoprotein must undergo farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyzes this modification, farnesyl protein transferase (FPTase), have therefore been suggested as anticancer agents for tumors in which Ras contributes to transformation. The tetrapeptide analog L-731,735 is a potent and selective inhibitor of FPTase in vitro. A prodrug of this compound, L-731,734, inhibited Ras processing in cells transformed with v-ras. L-731,734 decreased the ability of v-ras-transformed cells to form colonies in soft agar but had no effect on the efficiency of colony formation of cells transformed by either the v-raf or v-mos oncogenes. The results demonstrate selective inhibition of ras-dependent cell transformation with a synthetic organic inhibitor of FPTase.
Kohl
N E
NE
Department of Cancer Research, Merck Research Laboratories, West Point, PA 19486.
Mosser
S D
SD
deSolms
S J
SJ
Giuliani
E A
EA
Pompliano
D L
DL
Graham
S L
SL
Smith
R L
RL
Scolnick
E M
EM
Oliff
A
A
Gibbs
J B
JB
D019883:Alkyl and Aryl Transferases; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D051231:Farnesyltranstransferase; D011905:Genes, ras; D015513:Oncogene Proteins / Q000378:metabolism*; D017368:Protein Prenylation / Q000187:drug effects*; D051381:Rats; D014166:Transferases / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D004151:Dipeptides; D015513:Oncogene Proteins; C081841:L 731735; C081840:L 731734; D014166:Transferases; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase