Development of Novel Amides as Noncovalent Inhibitors of Immunoproteasomes

The development of immunoproteasome-selective inhibitors is a promising strategy for treating hematologic malignancies, autoimmune and inflammatory diseases. In this context, we report the design, synthesis, and biological evaluation of a new series of amide derivatives as immunoproteasome inhibitors. Notably, the designed compounds act as noncovalent inhibitors, which might be a promising therapeutic option because of the lack of drawbacks and side effects associated with irreversible inhibition. Among the synthesized compounds, we identified a panel of active inhibitors with K-i values in the low micromolar or sub-micromolar ranges toward the beta 5i and/or beta 1i subunits of immunoproteasomes. One of the active compounds was shown to be the most potent and selective inhibitor with a K-i value of 21 nm against the single beta 1i subunit. Docking studies allowed us to determine the mode of binding of the molecules in the catalytic site of immunoproteasome subunits.