Polybromo‑1 Bromodomain Inhibitor Selectivity Is Mediated by a Unique Ligand-Binding Pocket.

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Therapeutics

Background:

• Polybromo-1 (PBRM1) is crucial for the PBAF chromatin remodeling complex, regulating gene transcription via its bromodomains.
• Targeting PBRM1 bromodomains shows promise for treating prostate and clear cell renal cell carcinomas.
• Existing PBRM1 inhibitors often lack selectivity, binding to related SMARCA2/4 bromodomains.

Purpose of the Study:

• To elucidate the molecular basis of selectivity for novel PBRM1 bromodomain inhibitors.
• To identify key residues and binding interactions responsible for PBRM1-specific inhibition.
• To evaluate the therapeutic potential of selective PBRM1 inhibitors in cancer models.

Main Methods:

• X-ray crystallography to determine the structure of PBRM1-BD2 bound to the inhibitor PB16.
• Site-directed mutagenesis to investigate the role of specific PBRM1 residues in inhibitor binding.
• Cell-based assays to assess the activity of PB16 in PBRM1-dependent cancer models.

Main Results:

• The X-ray crystal structure revealed the binding mode of the selective inhibitor PB16 to PBRM1-BD2.
• Mutagenesis identified a unique tyrosine residue in PBRM1 essential for creating a distinct binding pocket for selective inhibitors.
• PB16 demonstrated cell activity in PBRM1-dependent cancer models, unlike other selective inhibitors.

Conclusions:

• A unique tyrosine residue in PBRM1 is critical for selective inhibitor binding.
• The PBRM1 inhibitor PB16 exhibits promising anti-cancer activity in relevant models.
• PB16 represents a potential lead candidate for developing targeted cancer therapies.