α-Keto Phenylamides as P1′-Extended Proteasome Inhibitors

Authors

  • Constantin Voss,

    1. Clemens Schöpf Institute for Organic Chemistry & Biochemistry, Technische Universität Darmstadt, Alarich Weiss-Str. 4-8, 64287 Darmstadt (Germany)
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  • Christoph Scholz,

    1. Clemens Schöpf Institute for Organic Chemistry & Biochemistry, Technische Universität Darmstadt, Alarich Weiss-Str. 4-8, 64287 Darmstadt (Germany)
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  • Sabine Knorr,

    1. Computational Biology & Simulation, Technische Universität Darmstadt, Schnittspahnstr. 10, 64287 Darmstadt (Germany)
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  • Philipp Beck,

    1. Center of Integrated Protein Science at the Department of Chemistry, Chair of Biochemistry, Technische Universität München, Lichtenbergstr. 4, 85747 Garching (Germany)
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  • Dr. Martin L. Stein,

    1. Center of Integrated Protein Science at the Department of Chemistry, Chair of Biochemistry, Technische Universität München, Lichtenbergstr. 4, 85747 Garching (Germany)
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  • Dr. Andrea Zall,

    1. Clemens Schöpf Institute for Organic Chemistry & Biochemistry, Technische Universität Darmstadt, Alarich Weiss-Str. 4-8, 64287 Darmstadt (Germany)
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  • Dr. Ulrike Kuckelkorn,

    1. Institute of Biochemistry CCM, Charité Universitätsmedizin Berlin, Charitéplatz 1/Virchowweg 6, 10117 Berlin (Germany)
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  • Prof. Dr. Peter-Michael Kloetzel,

    1. Institute of Biochemistry CCM, Charité Universitätsmedizin Berlin, Charitéplatz 1/Virchowweg 6, 10117 Berlin (Germany)
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  • Prof. Dr. Michael Groll,

    1. Center of Integrated Protein Science at the Department of Chemistry, Chair of Biochemistry, Technische Universität München, Lichtenbergstr. 4, 85747 Garching (Germany)
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  • Prof. Dr. Kay Hamacher,

    1. Computational Biology & Simulation, Technische Universität Darmstadt, Schnittspahnstr. 10, 64287 Darmstadt (Germany)
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  • Prof. Dr. Boris Schmidt

    Corresponding author
    1. Clemens Schöpf Institute for Organic Chemistry & Biochemistry, Technische Universität Darmstadt, Alarich Weiss-Str. 4-8, 64287 Darmstadt (Germany)
    • Clemens Schöpf Institute for Organic Chemistry & Biochemistry, Technische Universität Darmstadt, Alarich Weiss-Str. 4-8, 64287 Darmstadt (Germany)

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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.

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