Discovery and Characterization of Novel Non-Hydroxamate HDAC11 Inhibitors

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Pharmacology

Background:

• Histone deacetylase 11 (HDAC11) is implicated in various diseases, including cancer and neurodegeneration.
• Existing HDAC11 inhibitors often use hydroxamic acids, which can be mutagenic.
• There is a need for selective, non-hydroxamate HDAC11 inhibitors with improved drug properties.

Purpose of the Study:

• To identify novel, potent, and selective non-hydroxamate HDAC11 inhibitors.
• To characterize the binding mechanisms and drug-like properties of identified inhibitors.

Main Methods:

• High-throughput screening of 10,281 diverse compounds.
• Biochemical assays to determine inhibitory potency (IC50) and selectivity.
• Molecular docking to elucidate zinc-chelating mechanisms.
• Assessment of physicochemical and pharmacokinetic properties.

Main Results:

• Identified two novel non-hydroxamate HDAC11 inhibitors: caffeic acid phenethyl ester (CAPE) and compound 9SPC045H03.
• Both compounds demonstrated micromolar inhibitory potency (IC50 = 1.5 and 2.3 µM) with fast, reversible binding and high isozyme selectivity.
• Molecular docking revealed unique zinc-chelating interactions distinct from hydroxamates.
• Compounds exhibit favorable drug-like properties, including good water solubility and adsorption.

Conclusions:

• CAPE and 9SPC045H03 represent promising starting points for developing selective, non-hydroxamate HDAC11 inhibitors.
• These compounds offer potential therapeutic applications in diseases associated with HDAC11.
• The distinct chelation mechanisms provide new avenues for inhibitor design.