Structure-Based Identification of Novel Histone Deacetylase 4 (HDAC4) Inhibitors.

Area of Science:

• Biochemistry
• Molecular Biology
• Medicinal Chemistry

Background:

• Histone deacetylases (HDACs) are crucial targets in cancer therapy.
• Current FDA-approved HDAC inhibitors lack specificity due to conserved catalytic pockets across HDAC classes.
• Targeting class-specific pockets is essential for developing more precise cancer drugs.

Purpose of the Study:

• To identify and target novel, class-specific pockets in Class IIa HDACs, focusing on HDAC4.
• To discover small molecules that bind to these unique pockets, offering a different mechanism of action compared to existing inhibitors.
• To evaluate the selectivity and efficacy of identified compounds against HDAC4 and other HDACs, and in cancer cell lines.

Main Methods:

• Utilized molecular modeling and ensemble docking to screen for compounds targeting potential allosteric pockets in HDAC4.
• Employed consensus scoring to prioritize potential drug candidates.
• Performed experimental binding assays to compare compound activity against HDAC4 and HDAC3.
• Assessed the efficacy of active compounds in human breast and urothelial carcinoma cell lines.

Main Results:

• Identified novel pockets specific to HDAC4 at the HDAC4-NCoR interface.
• Compound 88402 selectively inhibited HDAC4 but not HDAC3.
• Compounds 67436 and 134199 showed low micromolar IC50 values for HDAC4, comparable to SAHA, but were significantly weaker against HDAC3, indicating limited selectivity.
• Five compounds demonstrated activity against human breast and/or urothelial carcinoma cell lines.

Conclusions:

• The study presents a novel strategy for developing selective HDAC4 inhibitors by targeting class-specific pockets.
• Identified compounds provide a chemical basis for developing next-generation HDAC-targeted cancer therapies.
• This approach could lead to more effective and less toxic cancer treatments by improving drug specificity.