Mass spectrometry-based chemical proteomics is a powerful tool in the target discovery of small molecules. Here we present the application of this approach to define the target profile of bio-inspired synthetic benzo[k,l]xanthene lignans, endowed with interesting biological properties. Proteasome has been identified as a new main interactor for this class of compounds. A combination of molecular docking and in vitro and in cell fluorescence assays gave insights on the molecular mechanism of interaction, highlighting the the attitude of these lignans to inhibit the proteasome
