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Function-oriented biosynthesis of beta-lactone proteasome inhibitors in Salinispora tropica.

Abstract
The natural proteasome inhibitor salinosporamide A from the marine bacterium Salinispora tropica is a promising drug candidate for the treatment of multiple myeloma and mantle cell lymphoma. Using a comprehensive approach that combined chemical synthesis with metabolic engineering, we generated a series of salinosporamide analogues with altered proteasome binding affinity. One of the engineered compounds is equipotent to salinosporamide A in inhibition of the chymotrypsin-like activity of the proteasome yet exhibits superior activity in the cell-based HCT-116 assay.
AuthorsMarkus Nett, Tobias A M Gulder, Andrew J Kale, Chambers C Hughes, Bradley S Moore
JournalJournal of medicinal chemistry (J Med Chem) Vol. 52 Issue 19 Pg. 6163-7 (Oct 08 2009) ISSN: 1520-4804 [Electronic] United States
PMID19746976 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Lactones
  • Protease Inhibitors
  • Proteasome Inhibitors
  • Pyrroles
  • marizomib
Topics
  • Actinobacteria (genetics)
  • Inhibitory Concentration 50
  • Lactones (chemical synthesis)
  • Protease Inhibitors (chemical synthesis)
  • Proteasome Inhibitors
  • Protein Engineering
  • Pyrroles (chemical synthesis)
  • Structure-Activity Relationship

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