4r02

yCP in complex with BSc4999 (alpha-Keto Phenylamide)

spinqualitylabelsall models 4r02, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4r02 is a 28 chain structure with sequence from [1] and Saccharomyces cerevisiae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 3E5, MG Related: 4qtr, 4qux, 4quy, 4qv0, 4qv1, 4qv3, 4qv4, 4qv5, 4qv6, 4qv7, 4qv8, 4qv9, 4qvl, 4qvm, 4qvn, 4qvp, 4qvq, 1ryp, 4qwr, 4qws, 4qwx, 4qz0, 4qz1, 4qz2, 4qz3, 4qz5, 4qz6, 4qzx, 4qzz Activity: Proteasome endopeptidase complex, with EC number 3.4.25.1 Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed The major challenge for proteasome inhibitor design lies in achieving high selectivity for, and activity against, the target, which requires specific interactions with the active site. Novel ligands aim to overcome off-target-related side effects such as peripheral neuropathy, which is frequently observed in cancer patients treated with the FDA-approved proteasome inhibitors bortezomib (1) or carfilzomib (2). A systematic comparison of electrophilic headgroups recently identified the class of alpha-keto amides as promising for next generation drug development. On the basis of crystallographic knowledge, we were able to develop a structure-activity relationship (SAR)-based approach for rational ligand design using an electronic parameter (Hammett's sigma) and in silico molecular modeling. This resulted in the tripeptidic alpha-keto phenylamide BSc4999 [(S)-3-(benzyloxycarbonyl-(S)-leucyl-(S)-leucylamino)-5-methyl-2-oxo-N-(2,4-dimet hylphenyl)hexanamide, 6 a], a highly potent (IC50 =38 nM), cell-permeable, and slowly reversible covalent inhibitor which targets both the primed and non-primed sites of the proteasome's substrate binding channel as a special criterion for selectivity. The improved inhibition potency and selectivity of this new alpha-keto phenylamide makes it a promising candidate for targeting a wider range of tumor subtypes than commercially available proteasome inhibitors and presents a new candidate for future studies. alpha-Keto Phenylamides as P1'-Extended Proteasome Inhibitors.,Voss C, Scholz C, Knorr S, Beck P, Stein ML, Zall A, Kuckelkorn U, Kloetzel PM, Groll M, Hamacher K, Schmidt B ChemMedChem. 2014 Aug 1. doi: 10.1002/cmdc.201402244. PMID:25087721 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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