Synthesis Of Macrocyclic Alpha-Ketoamide As A Selective And Reversible Immunoproteasome Inhibitor

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 alpha-ketoamide warhead. This compound is a selective and reversible inhibitor of immunoproteasome subunits beta 1i and beta 5i and shows essentially no inhibition of constitutive proteasome subunits.[GRAPHICS]