2. Academic Validation
  3. Regression of castration-resistant prostate cancer by a novel compound QW07 targeting androgen receptor N-terminal domain

Regression of castration-resistant prostate cancer by a novel compound QW07 targeting androgen receptor N-terminal domain

  • Cell Biol Toxicol. 2020 Oct;36(5):399-416. doi: 10.1007/s10565-020-09511-x.
Shihong Peng 1,  Jie Wang 2,  Huang Chen 1,  Pan Hu 1,  Xiao-Long He 2,  Yundong He 1,  Minna Wang 1,  Wenshu Tang 1,  Qiurui He 3,  Ying-Ying Wang 2,  Jiayi Xie 1,  Dandan Guo 1,  Shancheng Ren 4,  Mingyao Liu 1,  Wen-Wei Qiu 5,  Zhengfang Yi 6
Affiliations

Affiliations

  • 1 East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
  • 2 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200241, China.
  • 3 Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, 712100, China.
  • 4 Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, 200241, China.
  • 5 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200241, China. wwqiu@chem.ecnu.edu.cn.
  • 6 East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China. zfyi@bio.ecnu.edu.cn.
PMID: 32002708 DOI: 10.1007/s10565-020-09511-x
Abstract

Androgen deprivation therapy (ADT) via surgical or chemical castration frequently fails to halt lethal castration-resistant prostate Cancer (CRPC), which is induced by multiple mechanisms involving constitutive Androgen Receptor (AR) splice variants, AR mutation, and/or de novo androgen synthesis. The AR N-terminal domain (NTD) possesses most transcriptional activity and is proposed as a potential target for CRPC drug development. We constructed a screening system targeting AR-NTD transcription activity to screening a compound library and identified a novel small molecule compound named QW07. The function evaluation and mechanism investigation of QW07 were carried out in vitro and in vivo. QW07 bound to AR-NTD directly, blocked the transactivation of AR-NTD, blocked interactions between co-regulatory proteins and androgen response elements (AREs), inhibited the expression of genes downstream of AR, and inhibited prostate Cancer growth in vitro and in vivo. QW07 was demonstrated as an AR-NTD-specific antagonist with the potential to inhibit both canonical and variant-mediated AR signaling to regress the CRPC xenografts and is proposed as a lead compound for a specific antagonist targeting AR-NTD.

Keywords

AR transcriptional complex; AR-NTD; CRPC; QW07.

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