Structure-activity relationships of noncovalent immunoproteasome β5i-selective dipeptides Journal Article

   


Authors: Zhan, W.; Singh, P. K.; Ban, Y.; Qing, X.; Ah Kioon, M. D.; Fan, H.; Zhao, Q.; Wang, R.; Sukenick, G.; Salmon, J.; Warren, J. D.; Ma, X.; Barrat, F. J.; Nathan, C. F.; Lin, G.
Article Title: Structure-activity relationships of noncovalent immunoproteasome β5i-selective dipeptides
Abstract: The immunoproteasome (i-20S) has emerged as a therapeutic target for autoimmune and inflammatory disorders and hematological malignancies. Inhibition of the chymotryptic β5i subunit of i-20S inhibits T cell activation, B cell proliferation, and dendritic cell differentiation in vitro and suppresses immune responses in animal models of autoimmune disorders and allograft rejection. However, cytotoxicity to immune cells has accompanied the use of covalently reactive β5i inhibitors, whose activity against the constitutive proteasome (c-20S) is cumulative with the time of exposure. Herein, we report a structure-Activity relationship study of a class of noncovalent proteasome inhibitors with picomolar potencies and 1000-fold selectivity for i-20S over c-20S. Furthermore, these inhibitors are specific for β5i over the other five active subunits of i-20S and c-20S, providing useful tools to study the functions of β5i in immune responses. The potency of these compounds in inhibiting human T cell activation suggests that they may have therapeutic potential. © 2020 American Chemical Society. All rights reserved.
Journal Title: Journal of Medicinal Chemistry
Volume: 63
Issue: 21
ISSN: 0022-2623
Publisher: American Chemical Society  
Date Published: 2020-11-12
Start Page: 13103
End Page: 13123
Language: English
DOI: 10.1021/acs.jmedchem.0c01520
PUBMED: 33095579
PROVIDER: scopus
PMCID: PMC8086754
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85095835874&doi=10.1021%2facs.jmedchem.0c01520&partnerID=40&md5=08c8fcdaf8de8c8877f9ccc50e0e038a
Notes: Article -- Export Date: 4 January 2021 -- Source: Scopus
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MSK Authors
  1. George D Sukenick
    23 Sukenick
  2. Rong Wang
    8 Wang
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