AU-15330 (AU15330) is a highly specific and VHL-dependent PROTAC degrader of SWI/SNF ATPase components (SMARCA2, SMARCA4 and PBRM1), shows preferential cytotoxicity in enhancer-binding transcription factor-addicted cancers at low nanomolar concentrations.
The PROTAC degrader, AU-15330, comprising a bait moiety that binds the bromodomain in SMARCA2 and SMARCA4 and a ligand moiety for the von Hippel–Lindau (VHL) ubiquitin ligase.
Treatment of several cell lines with AU-15330 led to time and dose-dependent degradation of SMARCA2, SMARCA4 and PBRM1, exhibited preferential cytotoxicity in enhancer-binding transcription factor-driven cancers.
AR and FOXA1-driven prostate cancer cells to be preferentially sensitive to AU-15330 (IC50<100 nM).
AU-15330 inhibits tumour growth in preclinical models of CRPC and synergizes with enzalutamide.
Inactivation of SWI/SNF ATPase induces a rapid, near-complete and targeted loss of chromatin accessibility at the core-enhancer circuitry of AR, FOXA1, MYC and ERG, thereby attenuating their cancer-promoting transcriptional programs and tempering the enhancer-wired supra-physiologic expression of driver oncogenes.