Selective immunoproteasome inhibitors with non-peptide scaffolds identified from structure-based virtual screening

Vinod Kasam, Na Ra Lee, Kyung Bo Kim, Chang Guo Zhan

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


As a major component of the crucial nonlysosomal protein degradation pathway in the cells, the proteasome has been implicated in many diseases such as Alzheimer's disease, Huntington's disease, inflammatory bowel diseases, autoimmune diseases, multiple myeloma (MM) and other cancers. There are two main proteasome subtypes: the constitutive proteasome which is expressed in all eukaryotic cells and the immunoproteasome which is expressed in immune cells and can be induced in other cell types. Majority of currently available proteasome inhibitors are peptide backbone-based, having short half-lives in the body. It is highly desirable to identify novel, immunoproteasome-selective inhibitors with non-peptide scaffolds for development of novel therapeutics. Through combined virtual screening and experimental studies targeting the immunoproteasome, we have identified a set of novel immunoproteasome inhibitors with diverse non-peptide scaffolds. Some of the identified inhibitors have significant selectivity for the immunoproteasome over the constitutive proteasome. Unlike most of the currently available proteasome inhibitors, these new inhibitors lacking electrophilic pharmacophores are not expected to form a covalent bond with proteasome after the binding. These non-peptide scaffolds may provide a new platform for future rational drug design and discovery targeting the immunoproteasome.

Original languageEnglish
Pages (from-to)3614-3617
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Issue number15
StatePublished - Aug 1 2014

Bibliographical note

Funding Information:
The research was supported in part by the NIH (Grants RC1MH088480 and R01CA128903 ), Kentucky Science & Engineering Foundation (Grant KSEF-925-RDE-008 ). The authors also acknowledge the Computer Center at University of Kentucky for supercomputing time on a Dell Supercomputer Cluster consisting of 388 nodes or 4,816 processors.


  • Immunoproteasome
  • Inhibitor identification
  • Non-peptide scaffold
  • Selective inhibitor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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