Promoting Androgen Receptor Degradation with Isoprenylated Xanthones

Introduction: The androgen receptor (AR) has been a target of prostate cancer for nearly seventy years. In the last several years there has been an interest in identifying compounds that promote degradation of the androgen receptor. Our current studies have focused on evaluating isoprenylated xanthones for enhancing AR degradation through a combination of inducing the unfolded protein response pathway and inhibiting selected kinases.

Material and Methods: A selection of natural xanthones from the mangosteen fruit (Garcinia mangostana) and semi-synthetic xanthones were utilized to establish a structure activity relationship for primary and secondary assays for AR degradation and off-target effects. The interaction of xanthones was assessed using fluorescence polarization cell-free assay and cell-based FRET assay. Xanthones were also evaluated for modulating ER stress markers including BiP along with androgen receptor degradation. Immunopreciptation and silencing of key proteins in the ER stress pathway were also utilized to enhance the understanding of xanthone induced AR degradation.

Results: The results of the studies suggest that selected xanthones can have a direct interaction with androgen receptor. Additional experiments identified the inhibition of key kinases associated with AR stability. The half maximal effective concentration (EC50) was established for disrupting AR and selected kinases. These studies were then correlated with in vivo mouse pharmacokinetic experiments to identify promising candidates for further evaluation. Furthermore, a robust activation of the ER stress pathway was observed concurrently with AR degradation.

Conclusion: Our results suggest that xanthones from the mangosteen and semi-synthetic xanthones may be beneficial for promoting degradation of the androgen receptor through a mechanism that incorporates the ER stress pathway. Future studies are focused on evaluating additional xanthones for AR degradation. Taken together, the results of the above experiments were used to prioritize promising compounds for promoting AR degradation.