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Issue 6, 2012
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Optimization of a series of dipeptides with a P3 β-neopentyl asparagine residue as non-covalent inhibitors of the chymotrypsin-like activity of human 20S proteasome

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Abstract

Inhibition of the proteasome by covalent inhibitors is a clinically proven anti-cancer therapy. We report here that dipeptides with a P3 neopentyl Asn residue are potent, reversible, non-covalent inhibitors selective for the chymotryptic activity of the 20S proteasome in vitro and in cells. The X-ray structure of compound 20 in complex with yeast 20S reveals the importance of hydrophobic bonding interactions of the neopentyl group within the S3 binding pocket of the 20S β5 sub-unit. Four compounds show comparable potencies to boronic acid inhibitors in a panel of assays.

Graphical abstract: Optimization of a series of dipeptides with a P3 β-neopentyl asparagine residue as non-covalent inhibitors of the chymotrypsin-like activity of human 20S proteasome

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Publication details

The article was received on 29 Feb 2012, accepted on 16 Apr 2012 and first published on 19 Apr 2012


Article type: Concise Article
DOI: 10.1039/C2MD20060K
Citation: Med. Chem. Commun., 2012,3, 710-719
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    Optimization of a series of dipeptides with a P3 β-neopentyl asparagine residue as non-covalent inhibitors of the chymotrypsin-like activity of human 20S proteasome

    C. Blackburn, C. Barrett, J. L. Blank, F. J. Bruzzese, N. Bump, L. R. Dick, P. Fleming, K. Garcia, P. Hales, M. Jones, J. X. Liu, M. Nagayoshi, D. S. Sappal, M. D. Sintchak, C. Tsu, C. Xia, X. Zhou and K. M. Gigstad, Med. Chem. Commun., 2012, 3, 710
    DOI: 10.1039/C2MD20060K

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