4R02

yCP in complex with BSc4999 (alpha-Keto Phenylamide)

Summary for 4R02

• Entry DOI: 10.2210/pdb4r02/pdb
• Related: 1RYP 4QTR 4QUX 4QUY 4QV0 4QV1 4QV3 4QV4 4QV5 4QV6 4QV7 4QV8 4QV9 4QVL 4QVM 4QVN 4QVP 4QVQ 4QWR 4QWS 4QWX 4QZ0 4QZ1 4QZ2 4QZ3 4QZ5 4QZ6 4QZX 4QZZ
• Related PRD ID: PRD_001244
• Descriptor: Proteasome subunit alpha type-2, Proteasome subunit beta type-4, Proteasome subunit beta type-5, ... (17 entities in total)
• Functional Keywords: cancer, proteasome, drug development, binding analysis, reversible covalent ligand, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Saccharomyces cerevisiae (Baker's yeast); More
• Cellular location: Cytoplasm: P23639 P22141 P30656 P23724 P30657 P38624 P23638 P40303 P32379 P40302 P21242 P21243 P25043 P25451
• Total number of polymer chains: 28
• Total formula weight: 732567.75

Authors

Voss, C.,Scholz, C.,Knorr, S.,Beck, P.,Stein, M.,Zall, A.,Kuckelkorn, U.,Kloetzel, P.-M.,Groll, M.,Hamacher, K.,Schmidt, B. (deposition date: 2014-07-29, release date: 2014-08-13, Last modification date: 2023-09-20)

Primary citation

Voss, C.,Scholz, C.,Knorr, S.,Beck, P.,Stein, M.L.,Zall, A.,Kuckelkorn, U.,Kloetzel, P.M.,Groll, M.,Hamacher, K.,Schmidt, B.
alpha-Keto Phenylamides as P1'-Extended Proteasome Inhibitors.
Chemmedchem, 9:2557-2564, 2014

PubMed Abstract: 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 α-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 σ) and in silico molecular modeling. This resulted in the tripeptidic α-keto phenylamide BSc4999 [(S)-3-(benzyloxycarbonyl-(S)-leucyl-(S)-leucylamino)-5-methyl-2-oxo-N-(2,4-dimethylphenyl)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 α-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.

PubMed: 25087721
DOI: 10.1002/cmdc.201402244

Experimental method

X-RAY DIFFRACTION (2.5 Å)