Selective androgen receptor degrader (SARD) to overcome antiandrogen resistance in castration-resistant prostate cancer

  1. Meng Wu
  2. Rongyu Zhang
  3. Zixiong Zhang
  4. Ning Zhang
  5. Chenfan Li
  6. Yongli Xie
  7. Haoran Xia
  8. Fangjiao Huang
  9. Ruoying Zhang
  10. Ming Liu
  11. Xiaoyu Li
  12. Shan Cen  Is a corresponding author
  13. Jinming Zhou  Is a corresponding author
  1. Chinese Academy of Medical Sciences & Peking Union Medical College, China
  2. Zhejiang Normal University, China
  3. Beijing Hospital, China

Abstract

In patients with castration-resistant prostate cancer (CRPC), clinical resistances such as androgen receptor (AR) mutation, AR overexpression, and AR splice variants (ARVs) limit the effectiveness of second-generation antiandrogens (SGAs). Several strategies have been implemented to develop novel antiandrogens to circumvent the occurring resistance. Here, we found and identified a bifunctional small molecule Z15, which is both an effective AR antagonist and a selective AR degrader. Z15 could directly interact with the ligand-binding domain (LBD) and activation function-1 region of AR, and promote AR degradation through the proteasome pathway. In vitro and in vivo studies showed that Z15 efficiently suppressed AR, AR mutants and ARVs transcription activity, downregulated mRNA and protein levels of AR downstream target genes, thereby overcoming AR LBD mutations, AR amplification, and ARVs-induced SGAs resistance in CRPC. In conclusion, our data illustrate the synergistic importance of AR antagonism and degradation in advanced prostate cancer treatment.

Data availability

Data Availability: All data generated or analysed during this study are included in the manuscript and supporting source files. The RNA sequence data could be found in the following link: https://bigd.big.ac.cn/gsa-human/browse/HRA000921. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD035721. PRIDE - Proteomics Identification Database (ebi.ac.uk).

The following data sets were generated

Article and author information

Author details

  1. Meng Wu

    Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Rongyu Zhang

    Department of Chemistry, Zhejiang Normal University, Jinhua, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Zixiong Zhang

    Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Ning Zhang

    Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Chenfan Li

    Department of Chemistry, Zhejiang Normal University, Jinhua, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Yongli Xie

    Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Haoran Xia

    Department of Urology, Beijing Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Fangjiao Huang

    Department of Chemistry, Zhejiang Normal University, Jinhua, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Ruoying Zhang

    Department of Chemistry, Zhejiang Normal University, Jinhua, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Ming Liu

    Department of Urology, Beijing Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Xiaoyu Li

    Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Shan Cen

    Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
    For correspondence
    shancen@imb.pumc.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
  13. Jinming Zhou

    Department of Chemistry, Zhejiang Normal University, Jinhua, China
    For correspondence
    zhoujinming@zjnu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1610-5061

Funding

National Natural Science Foundation of China (22077115,81672559,81311120299)

  • Jinming Zhou

National Natural Science Foundation of China (82104231)

  • Meng Wu

China Postdoctoral Science Foundation (2021M700504)

  • Meng Wu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments have been approved by the Ethics Committee of Nanjing Lambda Pharmaceutical Co.,Ltd (Reference number: IACUC-20210902).

Reviewing Editor

  1. Wafik S El-Deiry, Brown University, United States

Publication history

  1. Received: May 26, 2021
  2. Accepted: January 18, 2023
  3. Accepted Manuscript published: January 19, 2023 (version 1)

Copyright

© 2023, Wu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Meng Wu
  2. Rongyu Zhang
  3. Zixiong Zhang
  4. Ning Zhang
  5. Chenfan Li
  6. Yongli Xie
  7. Haoran Xia
  8. Fangjiao Huang
  9. Ruoying Zhang
  10. Ming Liu
  11. Xiaoyu Li
  12. Shan Cen
  13. Jinming Zhou
(2023)
Selective androgen receptor degrader (SARD) to overcome antiandrogen resistance in castration-resistant prostate cancer
eLife 12:e70700.
https://doi.org/10.7554/eLife.70700
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