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

Journal of Enzyme Inhibition and Medicinal Chemistry

Domenica Altavilla¹  Roberta Ettari²  Maria Zappalಠ Carla Di Chio²  Santina Maiorana²  Natasha Irrera³  Gabriele Pizzino³  Francesco Squadrito³  Alessandra Bitto³  Giovanni Pallio³ 

[1] Department of Biomedical Sciences, Dentistry, and Morphofunctional Sciences, University of Messina, Messina, Ital;Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy;Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy;

关键词: Immunoproteasome;    multiple myeloma;    cyclins;   

DOI  :  10.1080/14756366.2019.1594802

来源: publisher

【 摘 要 】

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.

【 授权许可】

CC BY