Abstract
The 2-aminobenzvlstatine derivative I is a 20S proteasome inhibitor of a novel chemical type identified by high throughput screening. The compound specifically inhibits the chymotrypsin-like catalytic activity of the human proteasome with an IC50 value in the micromolar range. Using the crystal structure of the yeast proteasome, we modeled the structure of the human proteasome in complex with 1. As one of the first applications of the model in our oncology programme targeting the proteasome, we designed an analogue of the inhibitor having enhanced stacking/hydrophobic interactions with the enzyme. One order of magnitude in inhibitory potency was gained.
MeSH terms
-
Amino Acids / chemistry
-
Antineoplastic Agents / chemical synthesis
-
Antineoplastic Agents / chemistry
-
Antineoplastic Agents / metabolism
-
Binding Sites
-
Cysteine Endopeptidases / metabolism
-
Drug Design
-
Enzyme Inhibitors / chemical synthesis
-
Enzyme Inhibitors / chemistry
-
Enzyme Inhibitors / metabolism
-
Humans
-
Models, Molecular*
-
Multienzyme Complexes / antagonists & inhibitors*
-
Multienzyme Complexes / metabolism
-
Oligopeptides / chemical synthesis
-
Oligopeptides / chemistry
-
Oligopeptides / metabolism
-
Proteasome Endopeptidase Complex
-
Protein Binding
-
Structure-Activity Relationship
Substances
-
Amino Acids
-
Antineoplastic Agents
-
Enzyme Inhibitors
-
Multienzyme Complexes
-
Oligopeptides
-
Cysteine Endopeptidases
-
Proteasome Endopeptidase Complex
-
statine