State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, China.
Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, China.
Mol Cancer Ther. 2020 Jun;19(6):1221-1231. doi: 10.1158/1535-7163.MCT-19-0578. Epub 2020 Mar 27.
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. , 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. , 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.
去势抵抗性前列腺癌（CRPC）是一种致命疾病，一旦患者对第二代抗雄激素产生耐药，治疗选择就很少。在 CRPC 中，BET 蛋白是 AR 和 MYC 介导的转录的关键调节剂，而 PLK1 抑制剂除了影响细胞周期外，还有可能下调 AR 和 MYC。因此，同步抑制 BET 和 PLK1 可能是治疗 CRPC 的一种有前途的方法。本研究开发了一种双重 BET 和 PLK1 抑制剂 WNY0824，对 BRD4 和 PLK1 具有纳摩尔和等效力的抑制作用。WNY0824 对 AR 阳性 CRPC 细胞表现出优异的增殖抑制活性，并诱导细胞凋亡。这些活性归因于其破坏 AR 转录程序和抑制 ETS 途径。此外，WNY0824 下调 MYC 并诱导有丝分裂异常。在恩扎卢胺耐药的 CRPC 异种移植模型中，口服 WNY0824 给药抑制肿瘤生长。这些发现表明，WNY0824 是一种选择性的双重 BET 和 PLK1 抑制剂，具有强大的抗 CRPC 致癌活性，并为开发其他新型双重 BET 和 PLK1 抑制药物提供了思路。
