Stubba, Daniel ; Bensinger, Dennis ; Steinbacher, Janika ; Proskurjakov, Lilia ; Salcedo Gómez, Álvaro ; Schmidt, Uwe ; Roth, Stefan ; Schmitz, Katja ; Schmidt, Boris (2024)
Cell‐Based Optimization of Covalent Reversible Ketoamide Inhibitors Bridging the Unprimed to the Primed Site of the Proteasome β5 Subunit.
In: ChemMedChem, 2019, 14 (23)
doi: 10.26083/tuprints-00015965
Artikel, Zweitveröffentlichung, Verlagsversion

Kurzbeschreibung (Abstract)

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.

Typ des Eintrags:	Artikel
Erschienen:	2024
Autor(en):	Stubba, Daniel ; Bensinger, Dennis ; Steinbacher, Janika ; Proskurjakov, Lilia ; Salcedo Gómez, Álvaro ; Schmidt, Uwe ; Roth, Stefan ; Schmitz, Katja ; Schmidt, Boris
Art des Eintrags:	Zweitveröffentlichung
Titel:	Cell‐Based Optimization of Covalent Reversible Ketoamide Inhibitors Bridging the Unprimed to the Primed Site of the Proteasome β5 Subunit
Sprache:	Englisch
Publikationsjahr:	9 Januar 2024
Ort:	Darmstadt
Publikationsdatum der Erstveröffentlichung:	2019
Ort der Erstveröffentlichung:	Weinheim
Verlag:	Wiley-VCH
Titel der Zeitschrift, Zeitung oder Schriftenreihe:	ChemMedChem
Jahrgang/Volume einer Zeitschrift:	14
(Heft-)Nummer:	23
DOI:	10.26083/tuprints-00015965
URL / URN:	https://tuprints.ulb.tu-darmstadt.de/15965
Zugehörige Links:	Verlags-DOI
Herkunft:	Zweitveröffentlichung DeepGreen
Kurzbeschreibung (Abstract):	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.
Alternatives oder übersetztes Abstract:	Alternatives Abstract Sprache Bridging the gap: We report the identification of novel covalent reversible binding P1′-site extended α-ketoamide inhibitors for the proteasome β5 subunit. The development was guided by a new in-cell proteasome inhibition assay and the lead compound was profiled in a Danio rerio embryo escape response assay showing superior properties in comparison to bortezomib. BODIPY conjugated activity-based probes give insight into in-cell localization and distribution in zebrafish embryos. Englisch
Freie Schlagworte:	20 S proteasome, α-ketoamides, cancer, drug discovery, ubiquitin
Status:	Verlagsversion
URN:	urn:nbn:de:tuda-tuprints-159655
Zusätzliche Informationen:	This article also appears in: Cancer Research
Sachgruppe der Dewey Dezimalklassifikatin (DDC):	000 Allgemeines, Informatik, Informationswissenschaft > 004 Informatik 500 Naturwissenschaften und Mathematik > 540 Chemie 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin, Gesundheit
Fachbereich(e)/-gebiet(e):	20 Fachbereich Informatik 20 Fachbereich Informatik > Visuelle Inferenz 07 Fachbereich Chemie 07 Fachbereich Chemie > Clemens-Schöpf-Institut > Fachgebiet Biochemie 07 Fachbereich Chemie > Clemens-Schöpf-Institut > Fachgebiet Biochemie > Biologische Chemie 07 Fachbereich Chemie > Clemens-Schöpf-Institut > Fachgebiet Organische Chemie
Hinterlegungsdatum:	09 Jan 2024 12:27
Letzte Änderung:	10 Jan 2024 09:17
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Zugehörige Links:	Verlags-DOI
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Verfügbare Versionen dieses Eintrags

• Cell‐Based Optimization of Covalent Reversible Ketoamide Inhibitors Bridging the Unprimed to the Primed Site of the Proteasome β5 Subunit. (deposited 09 Jan 2024 12:27) [Gegenwärtig angezeigt]
  • Cell‐Based Optimization of Covalent Reversible Ketoamide Inhibitors Bridging the Unprimed to the Primed Site of the Proteasome β5 Subunit. (deposited 24 Apr 2020 05:43)

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