Biological and Medicinal Chemistry

Aza-SAHA Derivatives are Selective Histone Deacetylase 10 Chemical Probes That Inhibit Polyamine Deacetylation and Phenocopy HDAC10 Knockout



We report the first well-characterized selective chemical probe for histone deacetylase 10 (HDAC10) with unprecedented selectivity over other HDAC isozymes. HDAC10 deacetylates polyamines and has a distinct substrate specificity, making it unique among the 11 zinc-dependent HDAC hydrolases. Taking inspiration from HDAC10 polyamine substrates, we systematically inserted an amino group (“aza-scan”) into the hexyl linker moiety of the approved drug Vorinostat (SAHA). This one atom replacement (C-->N) transformed SAHA from an unselective pan-HDAC inhibitor into a specific HDAC10 inhibitor. Optimization of the aza-SAHA structure yielded the HDAC10 chemical probe DKFZ-748, with potency and selectivity demonstrated by cellular and biochemical target-engagement, as well as thermal-shift, assays. Co-crystal structures of our aza-SAHA derivatives with HDAC10 provide a structural rationale for potency, and chemoproteomic profiling con-firmed cellular HDAC10-selectivity of DKFZ-748 across the target landscape of HDAC drugs. Treatment of cells with DKFZ-748, followed by quantification of selected polyamines, confirmed for the first time the suspected cellular function of HDAC10 as a polyamine deacetylase. Finally, in a polyamine-limited in vitro tumor model, DKFZ-748 showed dose-dependent growth inhibition of HeLa cells. We expect DKFZ-748 and related probes to enable further studies on the enigmatic biology of HDAC10 and acetylated polyamines in both physiological and pathological settings.

Version notes

Added chemoproteomic profiling of DKFZ-748 with an HDACi affinity matrix. Added docking of HDACi into HDAC6 and HDAC10 to help explain selectivity. Added cell proliferation data of HeLa cells under polyamine-limiting conditions. Overall revised the text and data representation.


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Supplementary material

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Supporting Information
Supplementary schemes, tables, and figures, detailed experimental procedures, compound characterization, and 1H and 13C NMR spectra of newly synthesized substances
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Helmholtz Drug Repurposing Library Screen
Screening data from co-treatment of the Helmholtz Drug Repurposing Library with DKFZ-757 in BE(2)-C cells.
Thumbnail image of NCI-60 Screen DKFZ-711.xlsx
NCI-60 Screen with DKFZ-711
Outcome of a screen against the NCI-60 cancer cell line panel with HDAC10 inhibitor DKFZ-711
Thumbnail image of HDAC10-728_complex_docked_748.pdb
Docking of DKFZ-748 into HDAC10
PDB model of DKFZ-748 docked into the crystal structure of the HDAC10-DKFZ-728 complex (PDB: 7SGK).
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Docking of SAHA into HDAC6
PDB model of SAHA docked into the crystal structure of the HDAC6-trichostatin A complex (PDB: 5EDU).
Thumbnail image of HDAC6_5edu_docked_711.pdb
Docking of DKFZ-711 into HDAC6
PDB model of DKFZ-711 docked into the crystal structure of the HDAC6-trichostatin A complex (PDB: 5EDU).