Discovery of Highly Selective Inhibitors of the Immunoproteasome Low Molecular Mass Polypeptide 2 (LMP2) Subunit

Building upon the success of bortezomib (VELCADE) and carfilzomib (KYPROLIS), the design of a next generation of inhibitors targeting specific subunits within the immunoproteasome is of interest for the treatment of autoimmune disease. There are three catalytic subunits within the immunoproteasome (...

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Bibliographic Details
Published in:ACS medicinal chemistry letters 2017-04, Vol.8 (4), p.413-417
Main Authors: Johnson, Henry W. B, Anderl, Janet L, Bradley, Erin K, Bui, John, Jones, Jeffrey, Arastu-Kapur, Shirin, Kelly, Lisa M, Lowe, Eric, Moebius, David C, Muchamuel, Tony, Kirk, Christopher, Wang, Zhengping, McMinn, Dustin
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Language:English
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Letter
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Summary:Building upon the success of bortezomib (VELCADE) and carfilzomib (KYPROLIS), the design of a next generation of inhibitors targeting specific subunits within the immunoproteasome is of interest for the treatment of autoimmune disease. There are three catalytic subunits within the immunoproteasome (low molecular mass polypeptide-7, -2, and multicatalytic endopeptidase complex subunit-1; LMP7, LMP2, and MECL-1), and a campaign was undertaken to design a potent and selective LMP2 inhibitor with sufficient properties to allow for sustained inhibition in vivo. Screening a focused library of epoxyketones revealed a series of potent dipeptides that were optimized to provide the highly selective inhibitor KZR-504 (12).
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.6b00496