title: Pseudodipeptide inhibitors of protein farnesyltransferase.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: deSolms
authors.forename: A A
authors.initials: AA
authors.lastname: Deana
authors.forename: E A
authors.initials: EA
authors.lastname: Giuliani
authors.forename: S L
authors.initials: SL
authors.lastname: Graham
authors.forename: N E
authors.initials: NE
authors.lastname: Kohl
authors.forename: S D
authors.initials: SD
authors.lastname: Mosser
authors.forename: A I
authors.initials: AI
authors.lastname: Oliff
authors.forename: D L
authors.initials: DL
authors.lastname: Pompliano
authors.forename: E
authors.initials: E
authors.lastname: Rands
authors.forename: T H
authors.initials: TH
authors.lastname: Scholz
mesh_terms: 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
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D010455:Peptides; D014166:Transferases; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; D018631:ras Proteins