Androgen receptor (AR) has been extensively established as a potential therapeutic target for nearly all stages of prostate cancer (PCa). However, acquired resistance to AR-targeted drugs inevitably develops and severely limits their clinical efficacy. Particularly, there currently exists no efficient treatment for patients expressing the constitutively active AR splice variants, such as AR-V7. Herein, we report the structure–activity relationship studies of 55 N-heterocycle-substituted hydantoins, which identified the structural motifs required for AR/AR-V7 degradation. Among them, the most potent compound 27c exhibited selective AR/AR-V7 degradation over other hormone receptors and excellent antiproliferative activities in LNCaP and 22RV1 cells. RNA sequence analysis confirmed that 27c effectively suppressed transcriptional activity of the AR signaling pathway. Importantly, 27c demonstrated potent antitumor efficacy in an enzalutamide-resistant 22RV1 xenograft model. These results highlight the potential of 27c as a promising dual AR/AR-V7 degrader for overcoming drug resistance in advanced PCa expressing AR splice variants.

中文翻译：

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对晚期前列腺癌具有有效功效的新型单价 AR/AR-V7 双重降解剂的构效关系 (SAR) 研究

雄激素受体（AR）已被广泛确立为几乎所有阶段的前列腺癌（PCa）的潜在治疗靶点。然而，对 AR 靶向药物的获得性耐药不可避免地会发展并严重限制其临床疗效。特别是，目前对于表达组成型活性AR剪接变体（例如AR-V7）的患者尚无有效的治疗方法。在此，我们报告了 55 个N-杂环取代的乙内酰脲的构效关系研究，确定了 AR/AR-V7 降解所需的结构基序。其中，最有效的化合物27c比其他激素受体表现出选择性AR/AR-V7降解作用，并在LNCaP和22RV1细胞中表现出优异的抗增殖活性。 RNA序列分析证实27c有效抑制AR信号通路的转录活性。重要的是，27c在恩杂鲁胺耐药的 22RV1 异种移植模型中表现出有效的抗肿瘤功效。这些结果凸显了27c作为一种有前景的双 AR/AR-V7 降解剂的潜力，用于克服表达 AR 剪接变体的高级 PCa 的耐药性。