Non-thiol farnesyltransferase inhibitors: utilization of an aryl binding site by 5-arylacryloylaminobenzophenones.
We recently described a novel aryl binding site of farnesyltransferase. The 2-naphthylacryloyl residue was developed as an appropriate substituent for our benzophenone-based AAX-peptidomimetic capable of occupying this binding site, resulting in a non-thiol farnesyltransferase inhibitor with nanomolar activity. The activity of this inhibitor is readily explained on the basis of docking studies which show the 2-naphthyl residue fitting into the aryl binding site.
Mitsch
Andreas
A
Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, D-35032 Marburg, Germany.
Böhm
Markus
M
Wissner
Pia
P
Sattler
Isabel
I
Schlitzer
Martin
M
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D001577:Benzophenones / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D051231:Farnesyltranstransferase; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008958:Models, Molecular; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology; D011485:Protein Binding; D013329:Structure-Activity Relationship; D015003:Yeasts / Q000201:enzymology
D001577:Benzophenones; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase