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

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.