Details

Autor(en) / Beteiligte

• Beck, Philipp
• Reboud-Ravaux, Michèle
• Groll, Michael

Titel

Identification of a β1/β2-Specific Sulfonamide Proteasome Ligand by Crystallographic Screening

Ist Teil von

• Angewandte Chemie (International ed.), 2015-09, Vol.54 (38), p.11275-11278

Ort / Verlag

Weinheim: WILEY-VCH Verlag

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. Crystal clear: A non‐peptidic sulfonamide was identified as a proteasome ligand in a crystallographic screening approach for inhibitors with a novel mode of action. The newly discovered binding site displays significant differences in size and polarity between the immuno‐ and constitutive proteasome.