Selective PARP2 inhibitor disrupting PARP2-FOXA1 interaction to inhibit androgen receptor signaling in prostate cancer

Currently targeting androgen receptor (AR) pathways is the primary treatments for advanced prostate cancer (PCa). However, resistance to AR pathway inhibitors and emergence of castration-resistant prostate cancer (CRPC) remain a significant clinical challenge. We previously found that PARP2 interacts with FOXA1 to facilitate the recruitment of AR to genome-wide prostate-specific enhancer regions. Selective disruption of the PARP2-FOXA1 interaction inhibited AR signaling and PCa growth. However, lack of selectivity and potency of existing PARP2/FOXA1-targeting agents and uncertainty of the functional importance of PARP2-FOXA1 binding have limited our study. To address these gaps, we developed a potent small molecule inhibitor UMB-J17 that disrupts PARP2-FOXA1 interaction. In this study, we demonstrated that UMB-J17 competes with FOXA1 for the same PARP2 binding sites, and significantly suppresses AR signaling and PCa cell growth without involving AR-ligand binding. Preclinical studies demonstrated that UMB-J17 exerts potent anti-tumor effects in both in vitro and in vivo CRPC models. UMB-17 also exhibits potent synthetic effect with AR pathway inhibitors in enzalutamide-resistant CRPC models. Furthermore, UMB-J17 enhanced the synthetic lethality of PARP inhibition through AR signaling suppression in PCa. These findings identify UMB-J17 as a promising therapeutic agent that targets PARP2/FOXA1/AR axis for AR signaling inhibition, which is urgently needed to improve CRPC patient outcomes.