AU-15330

AU-15330 is a **proteolysis-targeting chimera (PROTAC) degrader** that selectively targets the **SWI/SNF chromatin remodeling complex ATPase subunits SMARCA2 and SMARCA4**, as well as **PBRM1**, for degradation via the von Hippel-Lindau (VHL) ubiquitin ligase pathway. The compound comprises a bait moiety that binds to the bromodomain in SMARCA2 and SMARCA4, coupled with a VHL ligand moiety. AU-15330 demonstrates preferential cytotoxicity in **androgen receptor (AR) and FOXA1-positive prostate cancer cells** at nanomolar concentrations, with IC50 values below 100 nM in these cell lines. Mechanistically, the degrader rapidly compacts cis-regulatory elements bound by oncogenic transcription factors including AR, FOXA1, ERG, and MYC, dislodging them from chromatin and disrupting super-enhancer and promoter looping interactions that drive oncogene expression. In preclinical models, AU-15330 demonstrates potent tumor growth inhibition in **castration-resistant prostate cancer (CRPC) xenografts** and synergizes with the AR antagonist enzalutamide, inducing disease remission without significant toxicity. The compound was developed by the **University of Michigan** and represents a novel therapeutic approach for targeting enhancer-addicted cancers by modulating chromatin accessibility at non-coding regulatory elements.

Other names

SMARCA2/4 PROTAC degraderSMARCA2/4 dual degraderSMARCA2/SMARCA4 PROTAC