Cell‐Based Optimization of Covalent Reversible Ketoamide Inhibitors Bridging the Unprimed to the Primed Site of the Proteasome β5 Subunit
The ubiquitin‐proteasome system (UPS) is an established therapeutic target for approved drugs to treat selected hematologic malignancies. While drug discovery targeting the UPS focuses on irreversibly binding epoxyketones and slowly‐reversibly binding boronates, optimization of novel covalent‐revers...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916368/ https://www.ncbi.nlm.nih.gov/pubmed/31675179 http://dx.doi.org/10.1002/cmdc.201900472 |
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author | Stubba, Daniel Bensinger, Dennis Steinbacher, Janika Proskurjakov, Lilia Salcedo Gómez, Álvaro Schmidt, Uwe Roth, Stefan Schmitz, Katja Schmidt, Boris |
author_facet | Stubba, Daniel Bensinger, Dennis Steinbacher, Janika Proskurjakov, Lilia Salcedo Gómez, Álvaro Schmidt, Uwe Roth, Stefan Schmitz, Katja Schmidt, Boris |
author_sort | Stubba, Daniel |
collection | PubMed |
description | The ubiquitin‐proteasome system (UPS) is an established therapeutic target for approved drugs to treat selected hematologic malignancies. While drug discovery targeting the UPS focuses on irreversibly binding epoxyketones and slowly‐reversibly binding boronates, optimization of novel covalent‐reversibly binding warheads remains largely unattended. We previously reported α‐ketoamides to be a promising reversible lead motif, yet the cytotoxic activity required further optimization. This work focuses on the lead optimization of phenoxy‐substituted α‐ketoamides combining the structure‐activity relationships from the primed and the non‐primed site of the proteasome β5 subunit. Our optimization strategy is accompanied by molecular modeling, suggesting occupation of P1′ by a 3‐phenoxy group to increase β5 inhibition and cytotoxic activity in leukemia cell lines. Key compounds were further profiled for time‐dependent inhibition of cellular substrate conversion. Furthermore, the α‐ketoamide lead structure 27 does not affect escape response behavior in Danio rerio embryos, in contrast to bortezomib, which suggests increased target specificity. |
format | Online Article Text |
id | pubmed-6916368 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-69163682019-12-17 Cell‐Based Optimization of Covalent Reversible Ketoamide Inhibitors Bridging the Unprimed to the Primed Site of the Proteasome β5 Subunit Stubba, Daniel Bensinger, Dennis Steinbacher, Janika Proskurjakov, Lilia Salcedo Gómez, Álvaro Schmidt, Uwe Roth, Stefan Schmitz, Katja Schmidt, Boris ChemMedChem Full Papers The ubiquitin‐proteasome system (UPS) is an established therapeutic target for approved drugs to treat selected hematologic malignancies. While drug discovery targeting the UPS focuses on irreversibly binding epoxyketones and slowly‐reversibly binding boronates, optimization of novel covalent‐reversibly binding warheads remains largely unattended. We previously reported α‐ketoamides to be a promising reversible lead motif, yet the cytotoxic activity required further optimization. This work focuses on the lead optimization of phenoxy‐substituted α‐ketoamides combining the structure‐activity relationships from the primed and the non‐primed site of the proteasome β5 subunit. Our optimization strategy is accompanied by molecular modeling, suggesting occupation of P1′ by a 3‐phenoxy group to increase β5 inhibition and cytotoxic activity in leukemia cell lines. Key compounds were further profiled for time‐dependent inhibition of cellular substrate conversion. Furthermore, the α‐ketoamide lead structure 27 does not affect escape response behavior in Danio rerio embryos, in contrast to bortezomib, which suggests increased target specificity. John Wiley and Sons Inc. 2019-11-12 2019-12-04 /pmc/articles/PMC6916368/ /pubmed/31675179 http://dx.doi.org/10.1002/cmdc.201900472 Text en © 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Full Papers Stubba, Daniel Bensinger, Dennis Steinbacher, Janika Proskurjakov, Lilia Salcedo Gómez, Álvaro Schmidt, Uwe Roth, Stefan Schmitz, Katja Schmidt, Boris Cell‐Based Optimization of Covalent Reversible Ketoamide Inhibitors Bridging the Unprimed to the Primed Site of the Proteasome β5 Subunit |
title | Cell‐Based Optimization of Covalent Reversible Ketoamide Inhibitors Bridging the Unprimed to the Primed Site of the Proteasome β5 Subunit |
title_full | Cell‐Based Optimization of Covalent Reversible Ketoamide Inhibitors Bridging the Unprimed to the Primed Site of the Proteasome β5 Subunit |
title_fullStr | Cell‐Based Optimization of Covalent Reversible Ketoamide Inhibitors Bridging the Unprimed to the Primed Site of the Proteasome β5 Subunit |
title_full_unstemmed | Cell‐Based Optimization of Covalent Reversible Ketoamide Inhibitors Bridging the Unprimed to the Primed Site of the Proteasome β5 Subunit |
title_short | Cell‐Based Optimization of Covalent Reversible Ketoamide Inhibitors Bridging the Unprimed to the Primed Site of the Proteasome β5 Subunit |
title_sort | cell‐based optimization of covalent reversible ketoamide inhibitors bridging the unprimed to the primed site of the proteasome β5 subunit |
topic | Full Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916368/ https://www.ncbi.nlm.nih.gov/pubmed/31675179 http://dx.doi.org/10.1002/cmdc.201900472 |
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