Inhibitory selectivity among class I HDACs has a major impact on inflammatory gene expression in macrophages

Area of Science:

• Biochemistry
• Pharmacology
• Molecular Biology

Background:

• Histone deacetylases (HDACs) are crucial in diseases like cancer and inflammation.
• Current HDAC inhibitors lack isoform selectivity, limiting therapeutic applications.
• HDAC 3 is implicated in inflammatory gene expression within class I HDACs.

Purpose of the Study:

• To synthesize and characterize novel HDAC inhibitors with selectivity for HDACs 1, 2, and 3.
• To understand the structure-activity relationships (SAR) governing isoform selectivity.
• To evaluate the anti-inflammatory potential of HDAC 3-selective inhibitors in cell-based models.

Main Methods:

• Synthesis of nine structural analogues based on the class I HDAC inhibitor Entinostat.
• Biochemical assays to determine inhibitory selectivity against HDACs 1, 2, and 3.
• Cell-based assays to assess the anti-inflammatory response and gene transcription modulation.

Main Results:

• Established SAR for class I HDAC inhibitors, linking structural features to isoform selectivity.
• Identified specific structural and conformational differences in the 'lid' region influencing HDAC 1 vs. HDAC 3 inhibition.
• HDAC 3-selective inhibitors did not elicit an anti-inflammatory response in macrophages, contrary to biochemical predictions.

Conclusions:

• Detailed SAR for class I HDAC inhibitors was elucidated.
• Isoform selectivity among class I HDACs was successfully linked to pro- and anti-inflammatory gene transcription.
• The study highlights the complexity of translating biochemical selectivity into cellular anti-inflammatory effects.