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

Journal of medicinal chemistry

PubMedID: 19746976

Nett M, Gulder TA, Kale AJ, Hughes CC, Moore BS. Function-oriented biosynthesis of beta-lactone proteasome inhibitors in Salinispora tropica. J Med Chem. 2009;52(19):6163-7.
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.