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Angew Chem Int Ed Engl. 2012 Aug 27;51(35):8708-20. doi: 10.1002/anie.201201616. Epub 2012 Jun 18.

Inhibitors for the immuno- and constitutive proteasome: current and future trends in drug development.

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Center for Integrated Protein Science at the Department of Chemistry, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany.


Proteolytic degradation is an essential cellular process which is primarily carried out by the 20S proteasome core particle (CP), a protease of 720 kDa and 28 individual subunits. As a result of its central functional role, the proteasome represents an attractive drug target that has been extensively investigated during the last decade and validated by the approval of bortezomib by the US Food and Drug Administration (FDA). Currently, several optimized second-generation proteasome inhibitors are being explored as anticancer drugs in clinical trials, and most of them target both constitutive proteasomes (cCPs) and immunoproteasomes (iCPs). However, selective inhibition of the iCPs, a distinct class of proteasomes predominantly expressed in immune cells, appears to be a promising therapeutic rationale for the treatment of autoimmune disorders. Although a few selective agents have already been identified, the recently determined crystal structure of the iCP will further promote the development and optimization of iCP-selective compounds.

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