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

Roberta EttariGiovanni PallioGabriele PizzinoNatasha IrreraMaria ZappalàSantina MaioranaCarla Di ChioDomenica AltavillaFrancesco SquadritoAlessandra Bitto
Published in: Journal of enzyme inhibition and medicinal chemistry (2019)
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 6 showed an ideal profile since it was able to inhibit both the chymotrypsin-like activities of the immunoproteasome with Ki values of 4.90 µM and 4.39 µM for β1i and β5i, respectively, coupled with an EC50 =17.8 µM against MM.1R cells. Compound 6 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.
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