Skip to main content
Log in

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

  • Original Article
  • Published:
Cell Biology and Toxicology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

ADT:

Androgen deprivation therapy

AF1:

Activation of function 1 domain

AF2:

Activation of function 2 domain

AR:

Androgen receptor

AREs:

Androgen response elements

CBP:

CREB-binding protein

CRPC:

Castration-resistant prostate cancer

CDX:

Bicalutamide

DBD:

DNA-binding domain

FSK:

Forskolin

HSP:

Heat shock proteins

IDPs:

Intrinsically disordered proteins

LBD:

Ligand-binding domain

NTD:

N-terminal domain

MDV:

Enzalutamide

PSA:

Prostate-specific antigen

SPR:

Surface plasmon resonance

SRB:

Sulforhodamine B

TSS:

Transcription start site

References

Download references

Acknowledgments

We thank Dr. Ying-Hao Sun (Department of Urology, Changhai Hospital) and Dr. Jie-Min Wong (Institute of Biomedical Sciences and School of Life Sciences, East China Normal University) for support of cell lines, plasmids, and scientific advice and thank all members of Mr. Liu’s Lab for scientific advice and helps.

Funding

This study was supported by National Key R&D Program of China (2018YFA0507001), National Natural Science Foundation of China (81773204, 81472788, 81830083, 81802970), Innovation program of Shanghai municipal education commission (2017-01-07-00-05-E00011), the Fundamental Research Funds for the Central Universities, China Postdoctoral Science Foundation (2018M632065), The Science and Technology Commission of Shanghai Municipality (11DZ2260300), Shanghai Science and Technology Council (18ZR1411200), Shenzhen Municipal Government of China (KQTD20170810160226082), and ECNU Public Platform for Innovation (011).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Wen-Wei Qiu or Zhengfang Yi.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(PDF 1230 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Peng, S., Wang, J., Chen, H. et al. Regression of castration-resistant prostate cancer by a novel compound QW07 targeting androgen receptor N-terminal domain. Cell Biol Toxicol 36, 399–416 (2020). https://doi.org/10.1007/s10565-020-09511-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10565-020-09511-x

Keywords

Navigation