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

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

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 ; Scholz, Christoph ; Knorr, Sabine ; Beck, Philipp ; Stein, Martin L. ; Zall, Andrea ; Kuckelkorn, Ulrike ; Kloetzel, Peter-Michael ; Groll, Michael ; Hamacher, Kay ; Schmidt, Boris
Type of entry: Bibliographie
Title: α-Keto Phenylamides as P1'-Extended Proteasome Inhibitors.
Language: English
Date: 2014
Journal or Publication Title: ChemMedChem
Volume of the journal: 9
Issue Number: 11
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.

Divisions: 10 Department of Biology
10 Department of Biology > Computational Biology and Simulation
Date Deposited: 03 Sep 2014 08:30
Last Modified: 24 Apr 2018 10:21
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