5-(Trifluoromethyl)-1,2,4-oxadiazole (TFMO)-based highly selective class IIa HDAC inhibitors exhibit synergistic anticancer activity in combination with bortezomib.

Autor: Asfaha Y; Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany., Bollmann LM; Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany., Skerhut AJ; Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany., Fischer F; Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany., Horstick N; Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany., Roth D; Department of Surgery (A), Medical Faculty, University Hospital of the Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany., Wecker M; Department of Surgery (A), Medical Faculty, University Hospital of the Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany., Mammen C; Institute of Biochemistry I, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany., Smits SHJ; Institute of Biochemistry I, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany; Center for Structural Studies, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany., Fluegen G; Department of Surgery (A), Medical Faculty, University Hospital of the Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany., Kassack MU; Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany., Kurz T; Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany. Electronic address: thomas.kurz@hhu.de.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Jan 05; Vol. 263, pp. 115907. Date of Electronic Publication: 2023 Nov 10.
DOI: 10.1016/j.ejmech.2023.115907
Abstrakt: Clinically used pan and class I HDACi cause severe side effects, whereas class IIa HDACi are less cytotoxic. Here, we present the synthesis and anticancer effects of a series of 5-(trifluoromethyl)-1,2,4-oxadiazole (TFMO)-based amides and alkoxyamides derived from the previously reported class IIa HDACi YAK540. The most active class IIa inhibitor 1a showed nanomolar inhibition of the class IIa enzymes 4, 5, 7 (IC 50 HDAC4: 12 nM) and high selectivity (selectivity index >318 for HDAC4) over non-class IIa HDACs. Instead of a hydroxamic acid group, 1a has a trifluoromethyloxadiazolyl (TFMO) moiety as a non-chelating Zinc-binding group (ZBG). Applying the Chou-Talalay-method we found an increased synergistic cytotoxic effect of 1a in combination with bortezomib in THP1 cells. 1a in combination with bortezomib enhanced expression of p21 leading to increased caspase-induced apoptosis. Eventually, growth inhibition by 1a of the head-neck cancer cell line Cal27 was increased upon HDAC4 overexpression in Cal27 in cell culture and using the in vivo chorioallantoic membrane model. The class IIa HDACi 1a outperforms previously described HDAC class IIa inhibitor YAK540 regarding anticancer effects and may constitute a novel option compared to pan and class I HDACi in anticancer combination treatments.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Matthias U. Kassack, Thomas Kurz reports financial support was provided by Deutsche Forschungsgemeinschaft. Yodita Asfaha, Lukas M. Bollmann, Alexander J. Skerhut, Fabian Fischer reports financial support was provided by Deutsche Forschungsgemeinschaft (DFG).
(Copyright © 2023. Published by Elsevier Masson SAS.)
Databáze: MEDLINE
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