Inhibitors for the Immuno- and Constitutive Proteasome: Current and Future Trends in Drug Development

• Published in: Angewandte Chemie International Edition Vol. 51; no. 35; pp. 8708 - 8720
• Main Authors: Huber, Eva Maria, Groll, Michael
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 27.08.2012; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - therapeutic use; autoimmune diseases; Autoimmune Diseases - drug therapy; Boronic Acids - chemistry; Boronic Acids - therapeutic use; Bortezomib; Crystal structure; Disorders; Doors; drug design; Drug Discovery - trends; Drugs; Foods; Humans; immunoproteasomes; Inductively coupled plasma; Inhibitors; Medical research; Medical services; Multiple Myeloma - drug therapy; Optimization; Proteasome Endopeptidase Complex - chemistry; Proteasome Endopeptidase Complex - metabolism; Proteasome Inhibitors - chemistry; Proteasome Inhibitors - therapeutic use; Protein Subunits - antagonists & inhibitors; Protein Subunits - metabolism; proteins; Pyrazines - chemistry; Pyrazines - therapeutic use; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Trends
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.201201616

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. Under arrest: The first immunoproteasome‐specific inhibitors were recently developed. The most potent one shows promise in the treatment of autoimmune diseases, thus opening the door for new clinical applications. Structure–affinity studies with the available immuno‐ and constitutive proteasome crystal structures will facilitate future drug development efforts.