Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 10, Issue 7, Pages 1086-1092Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.9b00233
Keywords
Proteasome; pseudopeptides; alpha-ketoamides; beta subunits inhibition
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- University of Ferrara
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Proteasome activity affects cell cycle progression as well as the immune response, and it is largely recognized as an attractive pharmacological target for potential therapies against several diseases. Herein we present the synthesis of a series of pseudodi/tripeptides bearing at the C-terminal position different alpha-ketoamide moieties as pharmacophoric units for the interaction with the catalytic threonine residue that sustains the proteolytic action of the proteasome. Among these, we identified the 1-naphthyl derivative 13c as a potent and selective inhibitor of the beta 5 subunit of the 20S proteasome, exhibiting nanomolar potency in vitro (beta 5 IC50 = 7 nM, beta 1 IC50 = 60 mu M, beta 2 IC50 > 100 mu M). Furthermore, it significantly inhibited proliferation and induced apoptosis of the human colorectal carcinoma cell line HCT116.
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