α-Aminoboronic Acid Moieties in Boro Dipeptides Modulate Proteasome Subunit Selectivity and Provide Access to...

Proteasomes regulate cellular protein homeostasis and are key targets in treating cancer, inflammation, and autoimmune diseases. The two main forms, the constitutive proteasome and immunoproteasome, each contain three catalytically active subunits with distinct substrate specificities. The first approved proteasome inhibitor, bortezomib, is nonselective and causes dose-limiting toxicity. Herein, we report dipeptide boronic acids with varying P1 residues, prepared using our recently developed method for α-aminoboronic acids formation. Most compounds inhibited various immuno/proteasome subunits in the low nanomolar range, displaying inhibition profiles distinct from bortezomib, ranging from β5i/β1i-selective to β5c/β5i-directed inhibitors. Although their cytotoxicity to cancer cells was not improved compared to bortezomib, selected compounds proved less toxic to noncancer cells and with anti-inflammatory activity comparable to that of zetomipzomib (KZR-616). The presented boro dipeptides with tailored P1 residues provide a basis for designing subunit-selective compounds with boronic acid as the warhead and optimized P2 and/or P3 positions.