Structure-based optimisation of 2-aminobenzylstatine derivatives: potent and selective inhibitors of the chymotrypsin-like activity of the human 20S proteasome.
We have identified 2-aminobenzylstatine derivatives that inhibit non-covalently the chymotrypsin-like activity of the human 20S proteasome. A structure-based optimisation approach has allowed us to improve the potency of this structural class of proteasome inhibitors from micromolar to nanomolar level. The new derivatives showed good selectivity against the trypsin-like and post-glutamyl-peptide hydrolytic activities of this enzyme.
Furet
Pascal
P
Oncology Research, Novartis Pharma Inc., CH-4002, Basel, Switzerland. pascal.furet@pharma.novartis.com
Imbach
Patricia
P
Fuerst
Peter
P
Lang
Marc
M
Noorani
Maria
M
Zimmermann
Johann
J
García-Echeverría
Carlos
C
D001593:Benzyl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D002918:Chymotrypsin / Q000037:antagonists & inhibitors*; D003546:Cysteine Endopeptidases; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D013329:Structure-Activity Relationship
D001593:Benzyl Compounds; D009097:Multienzyme Complexes; D011480:Protease Inhibitors; D002918:Chymotrypsin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex