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

ABSTRACT: 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

SUBMITTER: Nunez R 

PROVIDER: S-EPMC12516376 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature