Pseudodipeptide inhibitors of protein farnesyltransferase.
A series of pseudodipeptide amides are described that inhibit Ras protein farnesyltransferase (PFTase). These inhibitors are truncated versions of the C-terminal tetrapeptide (CAAX motif) of Ras that serves as the signal sequence for PFTase-catalyzed protein farnesylation. In contrast to CAAX peptidomimetics previously reported, these inhibitors do not have a C-terminal carboxyl moiety, yet they inhibit farnesylation in vitro at < 100 nM. Despite the absence of the X residue in the CAAX motif, which normally directs prenylation specificity, these pseudodipeptides are greater than 100-fold selective for PFTase over type 1 protein geranylgeranyltransferase.
deSolms
S J
SJ
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Deana
A A
AA
Giuliani
E A
EA
Graham
S L
SL
Kohl
N E
NE
Mosser
S D
SD
Oliff
A I
AI
Pompliano
D L
DL
Rands
E
E
Scholz
T H
TH
D016475:3T3 Cells; D019883:Alkyl and Aryl Transferases; D000577:Amides / Q000494:pharmacology; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051379:Mice; D010455:Peptides / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014166:Transferases / Q000037:antagonists & inhibitors*; D018631:ras Proteins / Q000378:metabolism
D000577:Amides; D004791:Enzyme Inhibitors; D010455:Peptides; D014166:Transferases; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; D018631:ras Proteins