2. Academic Validation
  3. Development of First-in-Class Dual Sirt2/HDAC6 Inhibitors as Molecular Tools for Dual Inhibition of Tubulin Deacetylation

Development of First-in-Class Dual Sirt2/HDAC6 Inhibitors as Molecular Tools for Dual Inhibition of Tubulin Deacetylation

  • J Med Chem. 2023 Nov 9;66(21):14787-14814. doi: 10.1021/acs.jmedchem.3c01385.
Laura Sinatra 1,  Anja Vogelmann 2,  Florian Friedrich 2,  Margarita A Tararina 3,  Emilia Neuwirt 4 5,  Arianna Colcerasa 2,  Philipp König 6,  Lara Toy 7,  Talha Z Yesiloglu 8,  Sebastian Hilscher 8 9,  Lena Gaitzsch 2,  Niklas Papenkordt 2,  Shiyang Zhai 6,  Lin Zhang 10,  Christophe Romier 11,  Oliver Einsle 10,  Wolfgang Sippl 8,  Mike Schutkowski 9,  Olaf Gross 4 5 12,  Gerd Bendas 6,  David W Christianson 3,  Finn K Hansen 1 6,  Manfred Jung 2,  Matthias Schiedel 7 13
Affiliations

Affiliations

  • 1 Institute for Drug Discovery, Medical Faculty, Leipzig University, Brüderstraße 34, 04103 Leipzig, Germany.
  • 2 Institute of Pharmaceutical Sciences, University of Freiburg, Albertstraße 25, 79104 Freiburg, Germany.
  • 3 Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.
  • 4 Institute of Neuropathology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Breisacherstraße 64, 79106 Freiburg, Germany.
  • 5 CIBSS-Centre for Integrative Biological Signalling Studies, University of Freiburg, Schänzlestraße 18, 79104 Freiburg, Germany.
  • 6 Department of Pharmaceutical & Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
  • 7 Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-University Erlangen-Nürnberg, Nikolaus-Fiebiger-Straße 10, 91058 Erlangen, Germany.
  • 8 Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, Wolfgang-Langenbeck-Straße 2-4, 06120 Halle (Saale), Germany.
  • 9 Department of Enzymology, Charles Tanford Protein Center, Institute of Biochemistry and Biotechnology, Martin-Luther-University Halle-Wittenberg, 06120 Halle, Germany.
  • 10 Institute of Biochemistry, University of Freiburg, Albertstraße 21, 79104 Freiburg, Germany.
  • 11 Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, CNRS UMR 7104, Inserm UMR-S 1258, 1 rue Laurent Fries, F-67400 Illkirch, France.
  • 12 Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, Breisacherstraße 64, 79106 Freiburg, Germany.
  • 13 Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstraße 55, 38106 Braunschweig, Germany.
PMID: 37902787 DOI: 10.1021/acs.jmedchem.3c01385
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-155392
    HDAC/Sirt2 Inhibitor