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Publication Abstract from PubMed

Proteasome inhibitors benefit patients with multiple myeloma and B cell-dependent autoimmune disorders but exert toxicity from inhibition of proteasomes in other cells. Toxicity should be minimized by reversible inhibition of the immunoproteasome beta5i subunit while sparing the constitutive beta5c subunit. Here we report beta5i-selective inhibition by asparagine-ethylenediamine (AsnEDA)-based compounds and present the high-resolution cryo-EM structural analysis of the human immunoproteasome. Despite inhibiting noncompetitively, an AsnEDA inhibitor binds the active site. Hydrophobic interactions are accompanied by hydrogen bonding with beta5i and beta6 subunits. The inhibitors are far more cytotoxic for myeloma and lymphoma cell lines than for hepatocarcinoma or non-activated lymphocytes. They block human B-cell proliferation and promote apoptotic cell death selectively in antibody-secreting B cells, and to a lesser extent in activated human T cells. Reversible, beta5i-selective inhibitors may be useful for treatment of diseases involving activated or neoplastic B cells or activated T cells.

Structure of human immunoproteasome with a reversible and noncompetitive inhibitor that selectively inhibits activated lymphocytes.,Santos RLA, Bai L, Singh PK, Murakami N, Fan H, Zhan W, Zhu Y, Jiang X, Zhang K, Assker JP, Nathan CF, Li H, Azzi J, Lin G Nat Commun. 2017 Nov 22;8(1):1692. doi: 10.1038/s41467-017-01760-5. PMID:29167449^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.