Benzodiazepine peptidomimetic inhibitors of farnesyltransferase.
A structural survey of protein Zn2+ binding geometries was instigated based upon the functional requirement of Ras farnesyltransferase for Zn2+. The Cys-X-X-Cys motif found in Zn(2+)-binding proteins such as aspartate transcarbamylase was used as a template to devise a bidentate-coordination model for Cys-A1-A2-X peptide inhibitors. Accordingly, replacement of the central dipeptide with the hydrophobic scaffold 3-amino-1-carboxymethyl-2,3-dihydro-5- phenyl-1H-1,4-benzodiazepin-2-one (BZA) yielded a peptidomimetic inhibitor, Cys(BZA)Met, of moderate potency (IC50 = 400 nM). N-Methylation of the cysteine amide improved potency almost 100-fold (IC50 = 0.3-1 nM). The increased affinity presumably correlates with a preferred conformation of the inhibitor which maximizes a hydrophobic interaction between the scaffold and the enzyme, and the proper presentation of cysteine and methionine to allow bidentate coordination at Zn2+. These non-peptide inhibitors have been shown to block farnesylation of the Ras protein in intact cells and provide lead compounds for the development of new cancer therapeutic agents.
Marsters
J C
JC
Department of Bioorganic Chemistry, Genentech Inc., South San Francisco, CA 94080.
McDowell
R S
RS
Reynolds
M E
ME
Oare
D A
DA
Somers
T C
TC
Stanley
M S
MS
Rawson
T E
TE
Struble
M E
ME
Burdick
D J
DJ
Chan
K S
KS
D019883:Alkyl and Aryl Transferases; D000595:Amino Acid Sequence; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000494:pharmacology*; D002463:Cell Membrane Permeability; D051231:Farnesyltranstransferase; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014166:Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D009842:Oligopeptides; D001569:Benzodiazepines; D014166:Transferases; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase