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Inhibitors of the Trypsin-Like Site of the Proteasome and Methods of Use Thereof

Proteasomes degrade the majority of proteins in mammalian cells, are involved in the regulation of multiple physiological functions, and are established targets of anti-cancer drugs. Proteasomes have three different types of active sites, chymotrypsin-like (β5), trypsin-like (β2), and caspase-like (β1). It has been suggested that the trypsin-like sites are important co-targets for anti-neoplastic agents.


Dartmouth and University of Leiden scientists have now developed cell-permeable inhibitors of the trypsin-like site of the proteasome. These compounds are peptide-based epoxyketones or vinyl sulfones (VS) that contain arginine or 4-aminomethylene-L-phenyalanine in the P1 position and inhibit trypsin-like β2/β2i sites of 26S proteasomes. These compounds selectively sensitize multiple myeloma cells to inhibitors of the chymotrypsin-like sites, including the anti-myeloma agents bortezomib and carfilzomib. Moreover, these compounds, when used in combination with inhibitors to the chymotryptic proteasome activity, overcome resistance of myeloma cells to bortezomib. Thus, these newly developed inhibitors can be used in the treatment of cancer and sensitization of malignant cells to therapeutic proteasome inhibitors that target β5/β5i sites of the proteasome.


These findings are claimed in US Patent Application Serial. No. 13/399,189. We are seeking an industrial partner to further refine and market this technology. (Ref: #J608)

Last Updated: 10/24/12