PFI-3

PFI-3 is a potent and highly selective small-molecule chemical probe that targets the bromodomains of **SMARCA2** (Brahma) and **SMARCA4** (BRG1), which are the catalytic ATPase subunits of the SWI/SNF (BAF) chromatin remodeling complex. It also exhibits significant affinity for the fifth bromodomain of **PBRM1** (Polybromo-1). Developed by Pfizer in collaboration with the Structural Genomics Consortium (SGC), PFI-3 acts as a competitive inhibitor of the acetyl-lysine binding pocket, effectively displacing the BAF complex from chromatin. While it is sometimes categorized as a bromodomain and extra-terminal motif (BET) inhibitor in broader contexts, it is specifically selective for the BAF family bromodomains over the BET family (BRD2/3/4). Preclinical research has explored PFI-3's potential in various cancers, including t(4;14)-positive multiple myeloma, where it displaces SMARCA2 and NSD2 from the *PTP4A3* promoter to inhibit cell viability, and clear cell renal cell carcinoma. Despite its high biochemical potency, PFI-3 often shows limited anti-proliferative activity as a monotherapy in many cell lines, suggesting that the bromodomain may not be the primary driver of SWI/SNF-mediated oncogenesis in all cellular contexts.