The androgen receptor AR antagonists, such as enzalutamide and apalutamide, are efficient therapeutics for the treatment of prostate cancer (PCa). Even though they are effective at first, resistance to both drugs occurs frequently. Resistance is mainly driven by aberrations of the AR signaling pathway including AR gene amplification and the expression of AR splice variants (e.g. AR-V7). This highlights the urgent need for alternative therapeutic strategies. Here, a total of 24 compounds were synthesized and biologically evaluated to disclose compound , exhibiting potent AR antagonistic activities (IC = 172.85 ± 21.33 nM), promising AR/AR-V7 protein degradation potency, and dual targeting site of probably AR (ligand-binding domain, LBD and N-terminal domain, NTD). It potently inhibits cell growth with IC values of 4.87 ± 0.52 and 2.07 ± 0.34 μM in the LNCaP and 22RV1 cell lines, respectively, and exhibited effective tumor growth inhibition (TGI = 50.9 %) in the 22RV1 xenograft study. These data suggest that has the potential for development as an AR/AR-V7 inhibitor with degradation ability to treat advanced prostate cancer.

中文翻译：

---

降解 AR/AR-V7 的新型选择性药物治疗晚期前列腺癌

雄激素受体 AR 拮抗剂，例如恩杂鲁胺和阿帕鲁胺，是治疗前列腺癌 (PCa) 的有效疗法。尽管它们一开始是有效的，但对这两种药物的耐药性经常发生。耐药性主要是由 AR 信号通路的异常驱动的，包括 AR 基因扩增和 AR 剪接变体（例如 AR-V7）的表达。这凸显了对替代治疗策略的迫切需要。在这里，总共合成了 24 种化合物并进行了生物学评估，以揭示化合物，表现出有效的 AR 拮抗活性 (IC = 172.85 ± 21.33 nM)、有希望的 AR/AR-V7 蛋白降解效力以及可能的 AR 的双重靶向位点（配体-结合域（LBD）和N端域（NTD）。它能有效抑制 LNCaP 和 22RV1 细胞系中的细胞生长，IC 值分别为 4.87 ± 0.52 和 2.07 ± 0.34 μM，并在 22RV1 异种移植研究中表现出有效的肿瘤生长抑制作用 (TGI = 50.9 %)。这些数据表明，具有开发为具有降解能力的 AR/AR-V7 抑制剂治疗晚期前列腺癌的潜力。