Optimization of a series of dipeptides with a P3 threonine residue as non-covalent inhibitors of the chymotrypsin-like activity of the human 20S proteasome

Autor:	Kenneth M. Gigstad, Khristofer Garcia, Paul Hales, Nancy Bump, Frank J. Bruzzese, Paul E. Fleming, Lawrence R. Dick, Zhigen Hu, Christopher Blackburn, Matthew Jones, Christopher Tsu, Michael D. Sintchak, Cynthia Barrett, Jane X. Liu, Jonathan L. Blank, Darshan S. Sappal
Rok vydání:	2010
Předmět:	Models Molecular Threonine Proteasome Endopeptidase Complex Stereochemistry Clinical Biochemistry Pharmaceutical Science Tripeptide Biochemistry 20s proteasome Residue (chemistry) chemistry.chemical_compound Drug Discovery Chymotrypsin Humans Chymotrypsin like Molecular Biology Dipeptide biology Organic Chemistry Active site Dipeptides Proteasome chemistry biology.protein Molecular Medicine
Zdroj:	Bioorganicmedicinal chemistry letters. 20(22)
ISSN:	1464-3405
Popis:	Starting from a tripeptide screening hit, a series of dipeptide inhibitors of the proteasome with Thr as the P3 residue has been optimized with the aid of crystal structures in complex with the β-5/6 active site of y20S. Derivative 25, (β5 IC(50)=7.4 nM) inhibits only the chymotryptic activity of the proteasome, shows cellular activity against targets in the UPS, and inhibits proliferation.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::aed960939ca4ea0080006c362ffe95f3 https://pubmed.ncbi.nlm.nih.gov/20875739 Zobrazit plný text záznamu Full Text from ScienceDirect