N-Arylalkyl pseudopeptide inhibitors of farnesyltransferase.
Inhibitors of Ras protein farnesyltransferase are described which are reduced pseudopeptides related to the C-terminal tetrapeptide of the Ras protein that signals farnesylation. Reduction of the carbonyl groups linking the first three residues of the tetrapeptide leads to active inhibitors which are chemically unstable. Stability can be restored by alkylating the central amine of the tetrapeptide. Studies of the SAR of these alkylated pseudopeptides with concomitant modification of the side chain of the third residue led to 2(S)-(2(S)-¿[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)- methylpentyl]naphthalen-1-ylmethylamino¿acetylamino)-4 -methylsulfany lbutyric acid (11), a subnanomolar inhibitor. The methyl ester (10) of this compound exhibited submicromolar activity in the processing assay and selectively inhibited anchorage-independent growth of Rat1 cells transformed by v-ras at 2.5-5 microM.
deSolms
S J
SJ
Departments of Medicinal Chemistry and Cancer Research, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Giuliani
E A
EA
Graham
S L
SL
Koblan
K S
KS
Kohl
N E
NE
Mosser
S D
SD
Oliff
A I
AI
Pompliano
D L
DL
Rands
E
E
Scholz
T H
TH
Wiscount
C M
CM
Gibbs
J B
JB
Smith
R L
RL
D016475:3T3 Cells; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004952:Esters / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051231:Farnesyltranstransferase; D051379:Mice; D018716:Molecular Mimicry; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009842:Oligopeptides / Q000737:chemistry*; D015689:Oncogene Protein p21(ras) / Q000037:antagonists & inhibitors; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship
C113174:2-amino-3-mercaptopropylamino-3-methylpentyl naphthalen-1-yl-methylamino acetylamino-4-methylsulfanylbutyric acid methy ester; D004791:Enzyme Inhibitors; D004952:Esters; D009281:Naphthalenes; D009842:Oligopeptides; D011355:Prodrugs; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D015689:Oncogene Protein p21(ras)