Journal
MEDCHEMCOMM
Volume 10, Issue 11, Pages 1958-1965Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c9md00365g
Keywords
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Funding
- Slovenian Research Agency [P1-0208, N1-0068]
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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 beta 5i 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.
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