Identification of a beta 1/beta 2-Specific Sulfonamide Proteasome Ligand by Crystallographic Screening - Biological Adaptation and Ageing Accéder directement au contenu
Article Dans Une Revue Angewandte Chemie International Edition Année : 2015

Identification of a beta 1/beta 2-Specific Sulfonamide Proteasome Ligand by Crystallographic Screening

Résumé

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 beta 1/beta 2-specific sulfonamide derivative that noncovalently binds between subunits beta 1 and beta 2. 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.

Dates et versions

hal-01544057 , version 1 (21-06-2017)

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Citer

Philipp Beck, Michele Reboud-Ravaux, Michael Groll. Identification of a beta 1/beta 2-Specific Sulfonamide Proteasome Ligand by Crystallographic Screening. Angewandte Chemie International Edition, 2015, 54 (38), pp.11275-11278. ⟨10.1002/anie.201505054⟩. ⟨hal-01544057⟩
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