Aza-SAHA Derivatives are Selective Histone Deacetylase 10 Chemical Probes That Inhibit Polyamine Deacetylation

Abstract

We report the first selective chemical probes 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 DKFZ-748, which has a double-digit nanomolar IC50 against HDAC10 in cells and >500-fold selectivity over the closest relative HDAC6 as well as the Class I enzymes (HDAC1, 2, 3, 8). Potency of our aza-SAHA derivatives is rationalized with HDAC10 co-crystal structures and demonstrated by cellular and biochemical target-engagement, as well as thermal-shift, assays. 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 poly-amine deacetylase. Selective HDAC10 chemical probes provide a valuable pharmacological tool for target validation and will enable further studies on the enigmatic biology of HDAC10 and acetylated polyamines. HDAC10-selective aza-SAHA derivatives are not cytotoxic, which opens the doors to novel therapeutic applications as immunomodulators or in combination cancer therapy.