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

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

  • Mol Cancer Ther. 2020 Jun;19(6):1221-1231. doi: 10.1158/1535-7163.MCT-19-0578.
Ying Xu # 1,  Qianqian Wang # 1,  Kunjie Xiao 1,  Zhihao Liu 1,  Lifeng Zhao 2,  Xuejiao Song 3,  Xi Hu 1,  Zhanzhan Feng 1,  Tiantao Gao 1,  Weiqiong Zuo 1,  Jun Zeng 1,  Ningyu Wang 4,  Luoting Yu 5
Affiliations

Affiliations

  • 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. yuluot@scu.edu.cn wangny-swjtu@swjtu.edu.cn.
  • 5 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, China. yuluot@scu.edu.cn wangny-swjtu@swjtu.edu.cn.
  • # Contributed equally.
PMID: 32220972 DOI: 10.1158/1535-7163.MCT-19-0578
Abstract

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.

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