Identification of a BAZ2A Bromodomain Hit Compound by Fragment Joining

Area of Science:

• Biochemistry
• Structural Biology
• Medicinal Chemistry

Background:

• Bromodomains of BAZ2A and BAZ2B are challenging drug targets among 61 human bromodomains.
• BAZ2A is a promising target for cancer therapy, while BAZ2B's role is less understood.

Purpose of the Study:

• To identify and characterize small molecules that bind to the BAZ2A bromodomain.
• To facilitate the development of novel therapeutics targeting BAZ2A in cancer.

Main Methods:

• Molecular docking campaigns to identify initial fragment binders.
• Competitive binding assays and X-ray crystallography for validation.
• Structure-based design of derivative compounds with improved affinity.

Main Results:

• A benzimidazole-triazole fragment was identified that binds to the BAZ2A acetyl lysine pocket.
• X-ray crystallography revealed the binding mode and identified a second proximal ligand.
• Designed benzimidazole-triazole derivatives demonstrated increased binding affinity for BAZ2A.

Conclusions:

• The benzimidazole-triazole scaffold represents a promising starting point for developing BAZ2A inhibitors.
• Structural insights enable rational design of potent BAZ2A-targeting cancer therapeutics.
• Engineered BAZ2A mutant facilitates high-resolution crystallographic studies for drug discovery.