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

Polybromo-1 (PBRM1) is a key subunit of the PBAF chromatin remodeling complex, linking histone lysine acetylation to transcriptional regulation through six tandem bromodomains. Targeting PBRM1 bromodomains offers therapeutic potential in prostate cancer and clear cell renal cell carcinoma. Most existing PBRM1 inhibitors also bind the structurally related SMARCA2/4 bromodomains and lack target selectivity. We and others recently developed selective PBRM1 bromodomain inhibitors that do not bind the SMARCA2/4 bromodomains. However, the key residues and binding interactions leading to selectivity for PBRM1 were unknown. Here, we solved an X-ray crystal structure of PBRM1-BD2 bound to our selective PBRM1 bromodomain inhibitor (PB16). Through mutagenesis, we identify a unique tyrosine residue in PBRM1 that creates a distinct binding pocket essential for selective inhibitor binding. Unlike GNE-235, another selective PBRM1 bromodomain inhibitor, PB16 demonstrates cell activity in PBRM1-dependent cancer models, making it a promising lead candidate to further develop for targeted cancer therapy.