选择性 PARP2 抑制剂通过破坏 PARP2-FOXA1 相互作用抑制前列腺癌中的雄激素受体信号

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.