Identification of mono- and bisubstrate inhibitors of protein farnesyltransferase and inducers of apoptosis from a pepticinnamin E library.
A library of 51 analogues of the naturally occurring protein farnesyltransferase inhibitor pepticinnamin E was investigated biologically. Several compounds with pronounced inhibitory activity were discovered with the lowest IC(50) value reaching 1 microM. The library contains inhibitors which are competitive to either farnesylpyrophosphate or the peptide substrate and a bisubstrate inhibitor. This activity is supported and rationalized by molecular modelling experiments and different binding modes of the inhibitors deduced from them. Several compounds induced apoptosis in a Ras-transformed tumour cell line, and in one case this correlated with farnesyltransferase-inhibiting activity.
Thutewohl
Michael
M
Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Str. 11, D-44227 Dortmund und Fachbereich 3, Organische Chemie, Universität Dortmund, Germany.
Kissau
Lars
L
Popkirova
Boriana
B
Karaguni
Ionna-Maria
IM
Nowak
Thorsten
T
Bate
Michael
M
Kuhlmann
Jürgen
J
Müller
Oliver
O
Waldmann
Herbert
H
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites; D045744:Cell Line, Tumor; D004285:Dogs; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D051231:Farnesyltranstransferase; D006801:Humans; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology*; D019151:Peptide Library; D051381:Rats; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D018631:ras Proteins / Q000378:metabolism
D004791:Enzyme Inhibitors; D009842:Oligopeptides; D019151:Peptide Library; C080552:pepticinnamin E; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D018631:ras Proteins