Identification of a new series of non-covalent proteasome inhibitors with selectivity for β5-subunits

Proteasome is a multisubunit, multicatalytic threonine protease complex with caspase-like (β1), trypsin-like (β2), and chymotrypsin-like (β5). It is responsible for the turnover of cellular proteins including those involved in signal transduction, cell cycle control, apoptosis and inflammation. Defects in the proteasome activity can lead to anarchic cell proliferation and tumors development. For these reasons, proteasome is a target of great interest in drug discovery for anticancer therapy.1 The majority of 20S inhibitors developed nowadays are peptide-based compounds endowed with a C-terminal electrophilic warhead that forms covalent adducts with the active site Thr1Oγ. However, very often this mechanism of action may lead to off-target interactions due to high reactivity of compounds. Non-covalent inhibitors provide an alternative mechanism for proteasome inhibition and, due to the rapid dissociation from the 20S subunits, may be devoid of all inherent drawbacks related to the covalent inhibition. In this context, we report a series of amide derivatives (1-2, Fig. 1) built on a constrained motif suitable for proteasomal β5 inhibition.2-3 Preliminary screening demonstrated that several derivatives are good inhibitors the proteasome β5 subunit with Ki values in the micromolar range. Docking models confirmed the expected non-covalent interaction with the target for this new class of amide derivatives