SMARCA2 degrader PRT7732

An orally bioavailable targeted protein degrader (TPD) of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 2 (SMARCA2; BRM), with potential antineoplastic activity. PRT7732 is comprised of an E3 ubiquitin ligase-binding moiety conjugated, via a chemical linker, to a SMARCA2-binding moiety. Upon oral administration of SMARCA2 degrader PRT7732, the SMARCA2-binding moiety specifically targets and binds to SMARCA2 and the E3 ubiquitin ligase-binding moiety targets and binds to the E3 ubiquitin ligase, thereby forming a ternary complex. This induces E3 ligase ubiquitination and proteasome-mediated degradation of SMARCA2. This may lead to the inhibition of the SWI/SNF (BRG1/BRM-associated factor; BAF) chromatin remodeling complex, disrupt chromatin remodeling and gene expression, and result in the downregulation of oncogenic pathways and the inhibition of tumor cell proliferation in SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4 (SMARCA4; BRG1)-deleted cancers. SMARCA2 and SMARCA4 are the primary ATPase components and mutually exclusive core catalytic subunits of the SWI/SNF chromatin remodeling complex, an important regulator of transcriptional programs and gene expression. SMARCA4 expression is absent in certain cancer cells, and these SMARCA4-deleted cancer cells depend on SMARCA2 for survival.