ABSTRACT
A series of beta-lactam derivatives has been designed and synthesized to inhibit the chymotrypsin-like activity of the human 20S proteasome. The most potent compounds of this new structural class of beta-subunit selective 20S proteasome inhibitors exhibit IC50 values in the low-nanomolar range and show good selectivity over the trypsin-like and post-glutamyl-peptide hydrolytic activities of the enzyme.
Subject(s)
Chymotrypsin/antagonists & inhibitors , Proteasome Inhibitors , Trypsin Inhibitors/chemical synthesis , Trypsin Inhibitors/pharmacology , beta-Lactams/chemical synthesis , beta-Lactams/pharmacology , Crystallography, X-Ray , Drug Design , Humans , Models, Molecular , Peptides/chemistry , Structure-Activity RelationshipABSTRACT
Proteasome inhibition is a therapeutic concept of current interest in anticancer research. We report here the design, synthesis, and biological characterization of prototypes of a new class of noncovalent proteasome inhibitors showing high activity in biochemical and cellular assays.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cysteine Proteinase Inhibitors/chemistry , Cysteine Proteinase Inhibitors/pharmacology , Multienzyme Complexes/antagonists & inhibitors , Binding Sites , Cell Division/drug effects , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/metabolism , Cysteine Proteinase Inhibitors/metabolism , Drug Screening Assays, Antitumor/methods , Humans , Hydrogen Bonding , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Multienzyme Complexes/chemistry , Multienzyme Complexes/metabolism , Oligopeptides/chemistry , Oligopeptides/metabolism , Oligopeptides/pharmacology , Proteasome Endopeptidase Complex , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
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.