title: Identification of mono- and bisubstrate inhibitors of protein farnesyltransferase and inducers of apoptosis from a pepticinnamin E library.
abstract: 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.
authors.affiliation: Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Str. 11, D-44227 Dortmund und Fachbereich 3, Organische Chemie, Universität Dortmund, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Thutewohl
authors.forename: Lars
authors.initials: L
authors.lastname: Kissau
authors.forename: Boriana
authors.initials: B
authors.lastname: Popkirova
authors.forename: Ionna-Maria
authors.initials: IM
authors.lastname: Karaguni
authors.forename: Thorsten
authors.initials: T
authors.lastname: Nowak
authors.forename: Michael
authors.initials: M
authors.lastname: Bate
authors.forename: Jürgen
authors.initials: J
authors.lastname: Kuhlmann
authors.forename: Oliver
authors.initials: O
authors.lastname: Müller
authors.forename: Herbert
authors.initials: H
authors.lastname: Waldmann
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D009842:Oligopeptides; D019151:Peptide Library; C080552:pepticinnamin E; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D018631:ras Proteins