Non-covalent immunoproteasome inhibitors induce cell cycle arrest in multiple myeloma MM.1R cells

Abstract

Proteasome inhibition is a promising strategy for the treatment of multiple myeloma; unfortunately, this disease is often associated with an increasing chemoresistance. One novel approach may be to target the immunoproteasome, a proteasomal isoform mainly present in cells of hematopoietic origin. We investigated the activity of a panel of amides against immunoproteasome core particles as potential agents for the treatment of multiple myeloma (MM). Amide <b>6</b> showed an ideal profile since it was able to inhibit both the chymotrypsin-like activities of the immunoproteasome with <i>K</i>_i values of 4.90 µM and 4.39 µM for <i>β</i>1i and <i>β</i>5i, respectively, coupled with an EC₅₀=17.8 µM against MM.1R cells. Compound <b>6</b> inhibited also ubiquitinated protein degradation and was able to act on different phases of MM cell cycle reducing the levels of cyclin A/CDK1, cyclin B/CDK1 and cyclin D/CDK4/6 complexes, which turns in cell cycle arrest.