Castration-resistant prostate cancer (CRPC) is a lethal disease with few treatment alternatives once patients become resistant to second-generation antiandrogens. In CRPC, BET proteins are key regulators of AR- and MYC-mediated transcription, while the PLK1 inhibitor potentially downregulates AR and MYC besides influencing the cell cycle. Therefore, synchronous inhibition of BET and PLK1 would be a promising approach for CRPC therapy. This study developed a dual BET and PLK1 inhibitor WNY0824 with nanomolar and equipotent inhibition of BRD4 and PLK1. In vitro, WNY0824 exhibited excellent antiproliferation activity on AR-positive CRPC cells and induced apoptosis. These activities are attributable to its disruption of the AR-transcriptional program and the inhibition of the ETS pathway. Furthermore, WNY0824 downregulated MYC and induced mitotic abnormality. In vivo, oral WNY0824 administration suppressed tumor growth in the CRPC xenograft model of enzalutamide resistance. These findings suggest that WNY0824 is a selective dual BET and PLK1 inhibitor with potent anti-CRPC oncogenic activity and provides insights into the development of other novel dual BET- and PLK1-inhibiting drugs.

中文翻译：

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新型 BET 和 PLK1 双重抑制剂 WNY0824 通过抑制转录因子功能和诱导有丝分裂异常，在 CRPC 中发挥有效的抗肿瘤作用


去势抵抗性前列腺癌（CRPC）是一种致命性疾病，一旦患者对第二代抗雄激素产生耐药性，几乎没有其他治疗选择。在 CRPC 中，BET 蛋白是 AR 和 MYC 介导的转录的关键调节因子，而 PLK1 抑制剂除了影响细胞周期外，还可能下调 AR 和 MYC。因此，同步抑制BET和PLK1将是CRPC治疗的一种有前途的方法。本研究开发了一种 BET 和 PLK1 双重抑制剂 WNY0824，对 BRD4 和 PLK1 具有纳摩尔等价抑制作用。在体外，WNY0824对AR阳性CRPC细胞表现出优异的抗增殖活性并诱导细胞凋亡。这些活性可归因于其对 AR 转录程序的破坏和对 ETS 途径的抑制。此外，WNY0824 下调 MYC 并诱导有丝分裂异常。在体内，口服 WNY0824 抑制恩杂鲁胺耐药的 CRPC 异种移植模型中的肿瘤生长。这些研究结果表明，WNY0824 是一种选择性 BET 和 PLK1 双重抑制剂，具有有效的抗 CRPC 致癌活性，并为其他新型 BET 和 PLK1 双重抑制药物的开发提供了见解。