Design and Synthesis of Dihydroxamic Acids as HDAC6/8/10 Inhibitors

Abstract

We report the synthesis and evaluation of a class of selective multitarget agents for the inhibition of HDAC6, HDAC8, and HDAC10. The concept for this study grew out of a structural analysis of the two selective inhibitors Tubastatin A (HDAC6/10) and PCI‐34051 (HDAC8), which we recognized share the same N‐benzylindole core. Hybridization of the two inhibitor structures resulted in dihydroxamic acids with benzyl‐indole and ‐indazole core motifs. These substances exhibit potent activity against HDAC6, HDAC8, and HDAC10, while retaining selectivity over HDAC1, HDAC2, and HDAC3. The best substance inhibited the viability of the SK‐N‐BE(2)C neuroblastoma cell line with an IC50 value similar to a combination treatment with Tubastatin A and PCI‐34051. This compound class establishes a proof of concept for such hybrid molecules and could serve as a starting point for the further development of enhanced HDAC6/8/10 inhibitors.

Strategies To Design Selective Histone Deacetylase Inhibitors

“…Strikingly, and in contrast to typically observed bidentate binding of hydroxamic acids with alkyl and vinyl linkers, all listed benzhydroxamic acids are bound in a monodentate fashion except bavarostat ( 63 ), AR‐42 ( 69 , PDB ID: 6UO3) and givinostat ( 70 ). Recent crystal structures of para ‐substituted benzhydroxamic acids with HDAC10 isoform, which is closely related to HDAC6, revealed mostly bidentate binding (PDB IDs: 6WBQ, 6WDV, 6WDX, 6WDW, 6WDY) except a bishydroxamic acid ( 71 ), which showed a rather monodentate binding (PDB ID: 6VNQ) [84b,86d] . Interestingly, a thiophene hydroxamic acid derivative ( 75 , Figure 4, a hydroxamic acid analog of compound 25 , Figure 2) has been previously reported to bind in a monodentate way in HDAC4 (PDB ID: 2VQM), but two para ‐substituted benzhydroxamic acids with human HDAC8 (PDB ID: 1VKG, 5FCW) demonstrated a canonical bidentate binding [18b,52,87] .…”

Histone deacetylase 10, a potential epigenetic target for therapy

“…The HDACIs tubastatin A and PCI-34051 have the same N-benzylindole core [ 150 , 152 ]. After hybridizing these two inhibitors, Morgen et al [ 153 ] synthesized dihydroxamic acids, which significantly suppressed the viability of neuroblastoma cells and played the role of potent inhibitor of HDAC10. Uba et al [ 137 ] constructed M0017, the best model of human HDAC10, and filtered out ZINC19749069, the highest rank compound from the ZINC database, which displayed high stability when docking it into the catalytic channel of an HDAC10 model with quisinostat.…”

X-ray Crystallographic Snapshots of Substrate Binding in the Active Site of Histone Deacetylase 10

“…HDAC10 inhibition is emerging as a strategy for cancer chemotherapy because inhibition blocks autophagy, thereby increasing the efficacy of cytotoxic drugs . The selectivity of inhibitor binding to HDAC10 over other HDAC isozymes can be enhanced by targeting interactions with the unique 3 10 helix and E274 in the HDAC10 active site. , For example, consider Tubastatin A, originally designed as a selective inhibitor of HDAC6 but subsequently discovered to be more selective for inhibition of HDAC10 . The 3 10 helix clamps the inhibitor in place while E274 makes an electrostatic interaction with the positively charged amino group of the inhibitor capping group .…”