Discovery and Characterization of Novel Non-Hydroxamate HDAC11 Inhibitors

Histone deacetylase 11 (HDAC11), the sole member of class IV HDACs, has gained prominence due to its unique enzymatic profile and pathological relevance in cancer, neurodegenerative, inflammatory diseases, and metabolic disorders. However, only a limited number of selective HDAC11 inhibitors have been identified, and many of these contain a potentially mutagenic hydroxamic acid as a zinc-chelating motif. Consequently, there is an imperative to identify potent and selective non-hydroxamate HDAC11 inhibitors with improved physicochemical properties. In this study, we conducted an extensive experimental high-throughput screening of 10,281 structurally diverse compounds to identify novel HDAC11 inhibitors. Two promising candidates, caffeic acid phenethyl ester (CAPE) and compound 9SPC045H03, both lacking a hydroxamic acid warhead, were discovered, showing micromolar inhibitory potency (IC₅₀ = 1.5 and 2.3 µM, respectively), fast and reversible binding, and remarkable isozyme selectivity. Molecular docking revealed distinct zinc-chelating mechanisms involving either carbonyl oxygen (CAPE) or pyridine nitrogen (9SPC045H03), in contrast to canonical hydroxamates. Both compounds are drug-like and exhibit favorable physicochemical and pharmacokinetic profiles, particularly beneficial water solubility and good adsorption, making them valuable starting points for further optimization. These findings open new avenues for the development of selective, non-hydroxamate HDAC11 inhibitors with potential therapeutic applications.