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Novel Dual BET and PLK1 Inhibitor WNY0824 Exerts Potent Antitumor Effects in CRPC by Inhibiting Transcription Factor Function and Inducing Mitotic Abnormality.

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机构： [1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, China. [2]Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, China. [3]West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China. [4]School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China.

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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. ©2020 American Association for Cancer Research.

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出版当年[2020]版：

大类 | 2 区医学

小类 | 2 区肿瘤学

最新[2023]版：

大类 | 2 区医学

小类 | 2 区肿瘤学

第一作者：

第一作者机构： [1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, China.

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通讯机构： [1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, China. [4]School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China. [*1]State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, 17 #3rd Section, Ren Min South Road, Chengdu 610041, China. [*2]School of Life Science and Engineering, Southwest Jiaotong University, No. 111 Nouth Section 1, Erhuan Road, Chengdu 610031, China

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