title: Identification of a β1/β2-specific sulfonamide proteasome ligand by crystallographic screening.
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.
authors.affiliation: Center for Integrated Protein Science Munich (CIPSM), Department of Chemistry, Technische Universität München, Lichtenbergstraße 4, 85748 Garching (Germany).
authors.forename: Philipp
authors.initials: P
authors.lastname: Beck
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR/CNRS 8256, Case 256, 7 Quai St-Bernard, 75252 Paris Cedex 05 (France).
authors.forename: Michèle
authors.initials: M
authors.lastname: Reboud-Ravaux
authors.affiliation: Center for Integrated Protein Science Munich (CIPSM), Department of Chemistry, Technische Universität München, Lichtenbergstraße 4, 85748 Garching (Germany). michael.groll@tum.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Groll
mesh_terms: D003461:Crystallography / Q000379:methods*; D008024:Ligands; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry*; D013449:Sulfonamides / Q000737:chemistry*
chemical_list: D008024:Ligands; D013449:Sulfonamides; D046988:Proteasome Endopeptidase Complex
keywords: crystallographic screening; drug discovery; proteasome; reversible inhibition; sulfonamides