Substrate-Guided Development of HDAC11-Selective Inhibitors Featuring α‑Amino Amide Zinc-Binding Groups.

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Drug Discovery

Background:

• Histone deacetylases (HDACs) are crucial in biological processes and are significant drug targets.
• Existing HDAC inhibitors (HDACi) often lack isoform selectivity and possess metabolically unstable zinc-binding groups (e.g., hydroxamic acid).
• HDAC11, a potent defatty-acylase, exhibits distinct substrate preferences compared to other HDACs.

Purpose of the Study:

• To design and synthesize novel HDAC inhibitors with high selectivity for HDAC11.
• To explore alternative zinc-binding groups beyond hydroxamic acid for improved metabolic stability.
• To develop inhibitors that leverage HDAC11's unique substrate preference via a selectivity tail.

Main Methods:

• Design of peptide-based inhibitors incorporating a fatty-acylated lysine side chain as a selectivity tail.
• Introduction of heteroatoms into the fatty acyl residue to create novel zinc-binding groups.
• Optimization of lead compounds to achieve potent and selective inhibition of HDAC11.
• In vitro enzymatic assays and cell-based activity assessments.

Main Results:

• A highly potent and selective HDAC11 inhibitor, compound 31, was identified.
• Compound 31 demonstrated low nanomolar inhibition against HDAC11 without cross-reactivity with other HDACs.
• The inhibitor was found to be active in cellular assays.
• The developed compounds suppressed substrate properties, enhancing selectivity.

Conclusions:

• The study successfully developed potent and selective HDAC11 inhibitors using a novel selectivity tail approach.
• The findings expand the repertoire of zinc-binding groups for HDAC inhibitor design.
• The selectivity tail strategy provides a facile route to selective defatty-acylase inhibitors, offering therapeutic potential.