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

Sinatra L, Vogelmann A, Friedrich F, Tararina MA, Neuwirt E, Colcerasa A, König P, Toy L, Yesiloglu TZ, Hilscher S, Gaitzsch L, Papenkordt N, Zhai S, Zhang L, Romier C, Einsle O, Sippl W, Schutkowski M, Gross O, Bendas G, Christianson DW, Hansen FK, Jung M, Schiedel M (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Journal of Medicinal Chemistry American Chemical Society

Book Volume: 66

Pages Range: 14787-14814

Journal Issue: 21

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.

Authors with CRIS profile

Lara Toy Lehrstuhl für Pharmazeutische Chemie Matthias Schiedel Lehrstuhl für Pharmazeutische Chemie

Involved external institutions

University of Pennsylvania US United States (USA) (US) Albert-Ludwigs-Universität Freiburg DE Germany (DE) Universitätsklinikum Leipzig DE Germany (DE) Universitätsklinikum Freiburg DE Germany (DE) Rheinische Friedrich-Wilhelms-Universität Bonn DE Germany (DE) Martin-Luther-Universität Halle-Wittenberg (MLU) DE Germany (DE) Université de Strasbourg (UDS) FR France (FR)

How to cite

APA:

Sinatra, L., Vogelmann, A., Friedrich, F., Tararina, M.A., Neuwirt, E., Colcerasa, A.,... Schiedel, M. (2023). Development of First-in-Class Dual Sirt2/HDAC6 Inhibitors as Molecular Tools for Dual Inhibition of Tubulin Deacetylation. Journal of Medicinal Chemistry, 66(21), 14787-14814. https://dx.doi.org/10.1021/acs.jmedchem.3c01385

MLA:

Sinatra, Laura, et al. "Development of First-in-Class Dual Sirt2/HDAC6 Inhibitors as Molecular Tools for Dual Inhibition of Tubulin Deacetylation." Journal of Medicinal Chemistry 66.21 (2023): 14787-14814.

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