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 mM and 4.39 mM for b1i and b5i, respectively, coupled with an EC50 ¼17.8 mM 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.

Non-covalent immunoproteasome inhibitors induce cell cycle arrest in multiple myeloma cells

R. Ettari
Primo
;
G. Pallio
Secondo
;
G. Pizzino;N. Irrera;M. Zappalà;S. Maiorana;C. Di Chio;D. Altavilla;F. Squadrito
Penultimo
;
A. Bitto
Ultimo
2019

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 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 mM and 4.39 mM for b1i and b5i, respectively, coupled with an EC50 ¼17.8 mM 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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Descrizione: Journal of enzyme inhibition 2019
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11570/3148090
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