Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 8, Issue 4, Pages 413-417Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.6b00496
Keywords
LMP2; immunoproteasome; constitutive proteasome; beta 1i; beta lc
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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 far 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).
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