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ID: ALA1268915

Journal: Bioorg Med Chem Lett

Title: Optimization of a series of dipeptides with a P3 threonine residue as non-covalent inhibitors of the chymotrypsin-like activity of the human 20S proteasome.

Authors: Blackburn C, Barrett C, Blank JL, Bruzzese FJ, Bump N, Dick LR, Fleming P, Garcia K, Hales P, Hu Z, Jones M, Liu JX, Sappal DS, Sintchak MD, Tsu C, Gigstad KM.

Abstract: Starting from a tripeptide screening hit, a series of dipeptide inhibitors of the proteasome with Thr as the P3 residue has been optimized with the aid of crystal structures in complex with the β-5/6 active site of y20S. Derivative 25, (β5 IC(50)=7.4 nM) inhibits only the chymotryptic activity of the proteasome, shows cellular activity against targets in the UPS, and inhibits proliferation.

CiteXplore: 20875739

DOI: 10.1016/j.bmcl.2010.09.032