Inhibiting Androgen Receptor Splice Variants with Cysteine-Selective Irreversible Covalent Inhibitors to Treat Prostate Cancer

Prostate cancer (PCa) affects over 250,000 men in the US. Androgen Receptor (AR) signaling inhibitors are the mainstay therapeutics for PCa. Advanced PCa that expresses AR splice variants (AR-SVs) does not respond to current therapeutic strategies. In this manuscript, we uncovered the physicochemical properties of the intrinsically-disordered transactivation domain of AR and AR-SV and developed novel AR irreversible covalent antagonists (SARICA) to the transactivation domain for the treatment of advanced PCa. SARICAs were also used to identify a potential binding region in the AR and AR-SV transactivation domain. Overall design: 22RV1 ATAC-Seq and RNA-Seq and LNCaP ATAC-Seq