Development of first-in-class dual Sirt2/HDAC6 inhibitors as molecular tools for dual inhibition of tubulin deacetylation

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Abstract: Dysregulation of both tubulin deacetylases sirtuin 2 (Sirt2) and the histone deacetylase 6 (HDAC6) has been associated with the pathogenesis of cancer and neurodegeneration, thus making these two enzymes promising targets for pharmaceutical intervention. Herein, we report the design, synthesis, and biological characterization of the first-in-class dual Sirt2/HDAC6 inhibitors as molecular tools for dual inhibition of tubulin deacetylation. Using biochemical in vitro assays and cell-based methods for target engagement, we identified Mz325 (33) as a potent and selective inhibitor of both target enzymes. Inhibition of both targets was further confirmed by X-ray crystal structures of Sirt2 and HDAC6 in complex with building blocks of 33. In ovarian cancer cells, 33 evoked enhanced effects on cell viability compared to single or combination treatment with the unconjugated Sirt2 and HDAC6 inhibitors. Thus, our dual Sirt2/HDAC6 inhibitors are important new tools to study the consequences and the therapeutic potential of dual inhibition of tubulin deacetylation

Standort
Deutsche Nationalbibliothek Frankfurt am Main
Umfang
Online-Ressource
Sprache
Englisch
Anmerkungen
Journal of medicinal chemistry. - 66, 21 (2023) , 14787–14814, ISSN: 1520-4804

Ereignis
Veröffentlichung
(wo)
Freiburg
(wer)
Universität
(wann)
2023
Urheber
Sinatra, Laura
Vogelmann, Anja
Friedrich, Florian
Tararina, Margarita A.
Neuwirt, Emilia
Colcerasa, Arianna
König, Philipp Thomas
Toy, Lara
Yesiloglu, Talha Z.
Hilscher, Sebastian
Gaitzsch, Lena
Papenkordt, Niklas
Zhai, Shiyang
Zhang, Lin
Romier, Christophe
Einsle, Oliver
Sippl, Wolfgang
Schutkowski, Mike
Groß, Olaf
Bendas, Gerd
Christianson, David W.
Hansen, Finn Kristian
Jung, Manfred
Schiedel, Matthias

DOI
10.1021/acs.jmedchem.3c01385
URN
urn:nbn:de:bsz:25-freidok-2409965
Rechteinformation
Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
Letzte Aktualisierung
14.08.2025, 11:00 MESZ

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