Identification of a BAZ2A Bromodomain Hit Compound by Fragment Joining

The bromodomains
of BAZ2A and BAZ2B (bromodomain adjacent to zinc
finger domain proteins 2) are among the most hard to drug of the 61
human bromodomains. While little is known about the role of BAZ2B,
there is strong evidence for the opportunity of targeting BAZ2A in
various cancers. Here, a benzimidazole–triazole fragment that
binds to the BAZ2A acetyl lysine pocket was identified by a molecular
docking campaign and validated by competitive binding assays and X-ray
crystallography. Another ligand was observed in close proximity by
soaking experiments using the BAZ2A bromodomain preincubated with
the benzimidazole–triazole fragment. The crystal structure
of BAZ2A with the two ligands was employed to design a few benzimidazole–triazole
derivatives with increased affinity. We also present the engineering
of a BAZ2A bromodomain mutant for consistent, high-resolution crystallographic
studies.