In recent years, the human immunoproteasome has emerged as an attractive therapeutic target for various diseases, leading to a growing interest in the discovery of immunoproteasome inhibitors that selectively target specific subunits. Herein we report the design, synthesis, and evaluation of a new immunoproteasome inhibitor that feature a macrocyclic ring containing an internal α-ketoamide warhead. This compound is a selective and reversible inhibitor of immunoproteasome subunits β1i and β5i and shows essentially no inhibition of constitutive proteasome subunits. [Figure not available: see fulltext.]
Bibliographical noteFunding Information:
This work was supported by the Center for Drug Design at the University of Minnesota. We thank Prof Rodney Johnson on the use of the ozone generator in his laboratory.
© 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.
- Immunoproteasome inhibitors
- Macrocyclic ketoamide
- Reversible covalent inhibitors