BiP-engaging xanthones from the mangosteen (Garcinia mangostana) induce androgen receptor degradation in prostate cancer cells.

Currently approved androgen receptor (AR) inhibitors for prostate cancer (PCa) target the ligand-binding domain (LBD) of the AR. These compounds cannot inhibit androgen receptor splice variant 7 (AR-V7), a truncated form of AR that is constitutively active in advanced PCa. Our previous studies demonstrated that α-mangostin, a xanthone derived from the fruit of Garcinia mangostana, promotes degradation of AR and AR-V7 through modulation of the chaperone binding immunoglobulin protein (BiP) in vitro and in vivo. Mangosteen contains more than 80 xanthones, and in this study we investigated whether additional xanthones can induce AR and AR-V7 degradation through direct BiP- engagement. Four fractions (F1-F4) were prepared from mangosteen extract, and their interactions with BiP were determined using surface plasmon resonance (SPR). Among them, F3 showed the highest binding affinity for BiP. We further evaluated additional xanthones isolated from these fractions. Among these compounds, α-mangostin exhibited the strongest binding affinity. Structure-activity relationship (SAR) analysis suggested that hydroxyl groups at C3 and a methoxy group at C7 contribute to BiP engagement. Consistent with these findings, α-mangostin and gartanin promoted degradation of AR and AR-V7 in 22Rv1 AR and AR-V7 HiBiT cells. Although BiP primarily functions through ATPase activity, α-mangostin did not affect its ATPase activity. Molecular docking of α-mangostin identified potential allosteric binding sites on BiP distinct from the ATPase pocket, suggesting that it may act as an allosteric modulator. Together, these findings identify mangosteen-derived xanthones as BiP-engaging compounds capable of promoting the degradation of AR and AR-V7 in PCa cells.