The proteasome represents a validated drug target for the treatment of cancer,
however, new types of inhibitors are required to tackle the development of
resistant tumors. Current fluorescence-based screening methods suffer from low
sensitivity and are limited to the detection of ligands with conventional
binding profiles. In response to these drawbacks, a crystallographic screening
procedure for the discovery of agents with a novel mode of action was utilized.
The optimized workflow was applied to the screening of a focused set of
compounds, resulting in the discovery of a β1/β2-specific sulfonamide
derivative that noncovalently binds between subunits β1 and β2. The binding
pocket displays significant differences in size and polarity between the immuno-
and constitutive proteasome. The identified ligand thus provides valuable
insights for the future structure-based design of subtype-specific proteasome
inhibitors.
