α‐Keto Phenylamides as P1′‐Extended Proteasome Inhibitors |
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Authors: | Constantin Voss Christoph Scholz Sabine Knorr Philipp Beck Dr Martin L Stein Dr Andrea Zall Dr Ulrike Kuckelkorn Prof?Dr Peter‐Michael Kloetzel Prof?Dr Michael Groll Prof?Dr Kay Hamacher Prof?Dr Boris Schmidt |
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Affiliation: | 1. Clemens Sch?pf Institute for Organic Chemistry & Biochemistry, Technische Universit?t Darmstadt, Alarich Weiss‐Str. 4‐8, 64287 Darmstadt (Germany);2. Computational Biology & Simulation, Technische Universit?t Darmstadt, Schnittspahnstr. 10, 64287 Darmstadt (Germany);3. Center of Integrated Protein Science at the Department of Chemistry, Chair of Biochemistry, Technische Universit?t München, Lichtenbergstr. 4, 85747 Garching (Germany);4. Institute of Biochemistry CCM, Charité Universit?tsmedizin Berlin, Charitéplatz 1/Virchowweg 6, 10117 Berlin (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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Keywords: | 20S proteasome cancer drug development Passerini reaction ubiquitin |
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