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

Publication Type:

Journal Article


J Am Chem Soc, Volume 144, Issue 41, p.18861-18875 (2022)


HeLa Cells, Histone Deacetylase Inhibitors, Histone Deacetylases, Humans, Hydroxamic Acids, Isoenzymes, Polyamines, Vorinostat, Zinc


<p>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 (&quot;aza-scan&quot;) into the hexyl linker moiety of the approved drug Vorinostat (SAHA). This one-atom replacement (C&rarr;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 , with potency and selectivity demonstrated by cellular and biochemical target engagement, as well as thermal shift assays. Cocrystal structures of our aza-SAHA derivatives with HDAC10 provide a structural rationale for potency, and chemoproteomic profiling confirmed exquisite cellular HDAC10-selectivity of across the target landscape of HDAC drugs. Treatment of cells with , followed by quantification of selected polyamines, validated for the first time the suspected cellular function of HDAC10 as a polyamine deacetylase. Finally, in a polyamine-limiting in vitro tumor model, showed dose-dependent growth inhibition of HeLa cells. We expect and related probes to enable further studies on the enigmatic biology of HDAC10 and acetylated polyamines in both physiological and pathological settings.</p>

HDAC10–SAHA complex, 7SGG; HDAC10-compound 14 complex, 7SGI; HDAC10–DKFZ-711 complex, 7SGJ; HDAC10–DKFZ-728 complex, 7SGK