Development and characterization of proteasome inhibitors

Kyung Bo Kim, Fabiana N. Fonseca, Craig M. Crews

Research output: Contribution to journalReview articlepeer-review

23 Scopus citations


Although many proteasome inhibitors have been either synthesized or identified from natural sources, the development of more sophisticated, selective proteasome inhibitors is important for a detailed understanding of proteasome function. We have found that antitumor natural product epoxomicin and eponemycin, both of which are linear peptides containing a α,β- epoxyketone pharmacophore, target proteasome for their antitumor activity. Structural studies of the proteasome-epoxomicin complex revealed that the unique specificity of the natural product toward proteasome is due to the α,β-epoxyketone pharmacophore, which forms an unusual six-membered morpholino ring with the amino terminal catalytic Thr-1 of the 20S proteasome. Thus, we believe that a facile synthetic approach for α,β-epoxyketone linear peptides provides a unique opportunity to develop proteasome inhibitors with novel activities. In this chapter, we discuss the detailed synthetic procedure of the α′,β′-epoxyketone natural product epoxomicin and its derivatives.

Original languageEnglish
Article number39
Pages (from-to)585-609
Number of pages25
JournalMethods in Enzymology
StatePublished - 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology


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