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Background: As a means of controlling levels of cellular proteins, eukaryotic organisms have evolved the ubiquitin-proteasome pathway, which selectively and rapidly degrades and eliminates undesired proteins. The availability of selective proteasome inhibitors has made it possible to understand the importance of this pathway and the critical role it plays in such cellular processes as cell cycle regulation, antigen presentation and the degradation of abnormally conformed or regulatory or membrane proteins. The ability to selectively inhibit proteasome function provides a mechanism to study basic cell biology as well exploring the applications of proteasome inhibition as a target for drug discovery.
Technology: Marine organisms are a rich source of natural products with unique structures and potent biological activities. UC Researchers have isolated and characterized one such product, Salinosporamide A (Sal A), which was discovered as a fermentation product from the marine actinomycete Salinispora tropica. By forming an irreversible, covalent adduct with the active site threonine of the 20S subunit of the proteasome, Sal A is able to potently and selectively inhibit all catalytic functions of the proteasome and thus represents a new biochemical tool that can be used to study basic cell biology or as a standard for drug discovery programs targeting proteasome inhibition.
Advantages:
- Significantly more potent than other commercially available proteasome inhibitors; IC50 values in the low to mid nM range
- 3-log specificity for the inhibition of proteasome proteolytic activities as compared to other proteases such as chymotrypsin, trypsin, catharsis A and catharsis B
- Well-characterized mechanism of binding and action
- Easily configured for sale as an individual reagent or within a kit
Keywords: Sal A, ubiquitin, ubiquitin-proteosome, degradation, chymotrypsin, trypsin, cathepsin A, cathepsin B, lactacystin, actinomycete, Salinispora tropica
Issued US Patents: 7,144,723; 7,179,834; 7,176,232; and 7,176,233.
Pending Patents: US 20080070273; Information on non-published and foreign applications applications available under confidentiality
Relevant Publications:
- Chauhan, D et. al. Cancer Cell 2005, 8: 407.
- Feling, R. H. et al. Angew. Chem. Int. Ed. 2003, 42: 355.
- Fenical, W. et. al, In Press. Bioorg. Med. Chem.
- Groll, M. et. al. J. Am. Chem. Soc. 2006, 128: 5136.
- Macherla, V. R., et. al., J. Med. Chem. 2005, 48: 3684.
Case Numbers: 2001-022 and 2001-208
Inquiries to: invent@ucsd.edu
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