Prostate cancer (PCa) is the most frequently diagnosed male malignant tumor and remains the second leading cause of male cancer mortality in western countries. The development of novel antiandrogens to circumvent the drug resistance in anti-PCa treatment is highly demanded. Herein, we identified that gossypol (GOS) specificly inhibited the AR signaling. Further optimization of GOS derivatives led to the discovery of compound XY-32. XY-32 efficiently inhibits AR signaling with the IC₅₀ of 1.23 μM. XY-32 downregulates both the full-length AR and the AR variable splice AR-V7 via suppressing the mRNA expression. It inhibits the proliferation of CRPC cells such as the LNCaP cells, the PC-3 cells, and enzalutamide resistance 22Rv1 cells. The work demonstrates the GOS derivatives represent a novel series of anti-androgen to conquer the acquired AR mutations or AR splice variants induced drug resistance of mCRPC.

前列腺癌（PCa）是最常被诊断出的男性恶性肿瘤，并且仍然是西方国家男性癌症死亡率的第二大原因。迫切需要开发新型抗雄激素药物以规避抗 PCa 治疗中的耐药性。在这里，我们发现棉酚 (GOS) 特异性抑制 AR 信号。GOS 衍生物的进一步优化导致化合物 XY-32 的发现。XY-32 通过 IC _{50有效抑制 AR 信号传导}1.23 μM。XY-32 通过抑制 mRNA 表达下调全长 AR 和 AR 可变剪接 AR-V7。它抑制 CRPC 细胞的增殖，例如 LNCaP 细胞、PC-3 细胞和恩杂鲁胺抗性 22Rv1 细胞。这项工作证明了 GOS 衍生物代表了一系列新的抗雄激素，以克服获得性 AR 突变或 AR 剪接变体诱导的 mCRPC 耐药性。