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α-Keto Phenylamides as P1'-Extended Proteasome Inhibitors.

Voss, Constantin and Scholz, Christoph and Knorr, Sabine and Beck, Philipp and Stein, Martin L. and Zall, Andrea and Kuckelkorn, Ulrike and Kloetzel, Peter-Michael and Groll, Michael and Hamacher, Kay and Schmidt, Boris (2014):
α-Keto Phenylamides as P1'-Extended Proteasome Inhibitors.
In: ChemMedChem, pp. 2557-2564, 9, (11), ISSN 1860-7187,
[Article]

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.

Item Type: Article
Erschienen: 2014
Creators: Voss, Constantin and Scholz, Christoph and Knorr, Sabine and Beck, Philipp and Stein, Martin L. and Zall, Andrea and Kuckelkorn, Ulrike and Kloetzel, Peter-Michael and Groll, Michael and Hamacher, Kay and Schmidt, Boris
Title: α-Keto Phenylamides as P1'-Extended Proteasome Inhibitors.
Language: English
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.

Journal or Publication Title: ChemMedChem
Volume: 9
Number: 11
Divisions: 10 Department of Biology
10 Department of Biology > Computational Biology and Simulation
Date Deposited: 03 Sep 2014 08:30
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