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Published on: March 3, 2021
Identification of a β1/β2-specific sulfonamide proteasome ligand by crystallographic screening
Philipp Beck1, Michèle Reboud-Ravaux2, Michael Groll3
1Center for Integrated Protein Science Munich (CIPSM), Department of Chemistry, Technische Universität München, Lichtenbergstraße 4, 85748 Garching (Germany).
Abstract:
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.
Insights
New proteasome inhibitors are crucial for overcoming cancer resistance. Crystallographic screening identified a novel sulfonamide derivative, offering insights for developing subtype-specific proteasome inhibitors.
Area of Science:
- Proteasome biology and drug discovery
- Structural biology and medicinal chemistry
Background:
- The proteasome is a validated cancer drug target.
- Existing inhibitors face challenges with resistant tumors and low-sensitivity screening methods.
- Novel inhibitors with unique binding mechanisms are needed.
Purpose of the Study:
- To develop an optimized crystallographic screening workflow for discovering novel proteasome inhibitors.
- To identify agents with unconventional modes of action against proteasome targets.
- To explore structure-based design strategies for subtype-specific inhibitors.
Main Methods:
- Utilized an optimized crystallographic screening procedure.
- Screened a focused set of chemical compounds.
- Analyzed ligand binding to proteasome subunits using structural data.
Main Results:
- Discovered a novel sulfonamide derivative with β1/β2 specificity.
- The identified ligand noncovalently binds between proteasome subunits β1 and β2.
- Observed significant differences in the binding pocket between immuno- and constitutive proteasomes.
Conclusions:
- The identified sulfonamide provides a novel class of proteasome inhibitor.
- Structural insights facilitate the design of subtype-specific proteasome inhibitors.
- Crystallographic screening is effective for discovering inhibitors with novel mechanisms.
