Androgen deprivation therapy (ADT) via surgical or chemical castration frequently fails to halt lethal castration-resistant prostate cancer (CRPC), which is induced by multiple mechanisms involving constitutive androgen receptor (AR) splice variants, AR mutation, and/or de novo androgen synthesis. The AR N-terminal domain (NTD) possesses most transcriptional activity and is proposed as a potential target for CRPC drug development. We constructed a screening system targeting AR-NTD transcription activity to screening a compound library and identified a novel small molecule compound named QW07. The function evaluation and mechanism investigation of QW07 were carried out in vitro and in vivo. QW07 bound to AR-NTD directly, blocked the transactivation of AR-NTD, blocked interactions between co-regulatory proteins and androgen response elements (AREs), inhibited the expression of genes downstream of AR, and inhibited prostate cancer growth in vitro and in vivo. QW07 was demonstrated as an AR-NTD-specific antagonist with the potential to inhibit both canonical and variant-mediated AR signaling to regress the CRPC xenografts and is proposed as a lead compound for a specific antagonist targeting AR-NTD.

通过手术或化学阉割的雄激素剥夺疗法 (ADT) 经常无法阻止致命的去势抵抗性前列腺癌 (CRPC)，这是由涉及组成型雄激素受体 (AR) 剪接变异、AR 突变和/或从头雄激素的多种机制诱发的合成。AR N 端结构域 (NTD) 具有最大的转录活性，被提议作为 CRPC 药物开发的潜在靶点。我们构建了一个针对 AR-NTD 转录活性的筛选系统来筛选化合物库，并鉴定出一种名为 QW07 的新型小分子化合物。对QW07进行了体外和体内功能评价和机制研究。QW07 直接与 AR-NTD 结合，阻断 AR-NTD 的反式激活，阻断共调节蛋白与雄激素反应元件 (ARE) 之间的相互作用，抑制 AR 下游基因的表达，并在体外和体内抑制前列腺癌的生长。QW07 被证明是一种 AR-NTD 特异性拮抗剂，具有抑制经典和变异介导的 AR 信号传导以逆转 CRPC 异种移植物的潜力，并被提议作为靶向 AR-NTD 的特异性拮抗剂的先导化合物。