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A focused structure–activity relationship study of psoralen-based immunoproteasome inhibitors

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Abstract

The immunoproteasome is a multicatalytic protease that is predominantly expressed in cells of hematopoietic origin. Its elevated expression has been associated with autoimmune diseases, various types of cancer, and inflammatory diseases. The development of immunoproteasome-selective inhibitors with non-peptidic scaffolds remains a challenging task. Here, we describe a focused series of psoralen-based inhibitors of the β5i subunit of the immunoproteasome with different substituents placed at position 4′. The most promising compound was further evaluated through changes at position 3 of the psoralen ring. Despite a small decrease in the inhibitory potency in comparison with the parent compound, we were able to improve the selectivity against other subunits of both the immunoproteasome and the constitutive proteasome. The most potent compounds discriminated between both proteasome types in cell lysates and also showed a decrease in cytokine secretion in peripheral blood mononuclear cells.

Graphical abstract: A focused structure–activity relationship study of psoralen-based immunoproteasome inhibitors

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Publication details

The article was received on 17 Jul 2019, accepted on 08 Sep 2019 and first published on 13 Sep 2019


Article type: Research Article
DOI: 10.1039/C9MD00365G
Med. Chem. Commun., 2019, Advance Article

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    A focused structure–activity relationship study of psoralen-based immunoproteasome inhibitors

    E. S. Schiffrer, I. Sosič, A. Šterman, J. Mravljak, I. M. Raščan, S. Gobec and M. Gobec, Med. Chem. Commun., 2019, Advance Article , DOI: 10.1039/C9MD00365G

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