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

31 July 2023, Version 2


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 (31) 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 31. In ovarian cancer cells, 31 evoked enhanced antiproliferative effects 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.


Drug Discovery
Click Chemistry
Medicinal Chemistry

Supplementary materials

Supporting Information
The Supporting Information includes supplementary figures, tables, NMR spectra, and HPLC chromatograms.


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Comment number 1, Guillaume Médard: Aug 04, 2023, 13:09

To put the work into more context for the readers, we would like to here mitigate the purported HDAC6 selectivities of some literature inhibitors described in figure 1. For instance "Ricolinostat is not a highly selective HDAC6 inhibitor" ( questions claims of the relevance of HDAC6 inhibition for some observed biological effects. "Target deconvolution of HDAC pharmacopoeia reveals MBLAC2 as common off-target" ( indicates MBLAC2 as a target of Nexturastat with very good potency. Would Mz325 exhibit unexplained phenotypes in the future (e.g. concerning extracellular vesicles), it would not be unlikely that MBLAC2 could be to blame, since Mz325 partially recapitulates the structure of Nexturastat A. May Mz325 have a bright future as a tool and more !

Matthias Schiedel :
Oct 03, 2023, 06:59

We thank Guillaume Médard for his important suggestions and have them in the updated version of our manuscript.