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Updated: Dec 29, 2025
Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
Regression of castration-resistant prostate cancer by a novel compound QW07 targeting androgen receptor N-terminal
Shihong Peng1, Jie Wang2, Huang Chen1
1East 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.
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.
Insights
A new drug, QW07, targets the androgen receptor N-terminal domain (AR-NTD) to combat castration-resistant prostate cancer (CRPC). This AR-NTD antagonist shows promise for treating advanced prostate cancer by inhibiting tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Androgen deprivation therapy (ADT) often fails in treating lethal castration-resistant prostate cancer (CRPC).
- Mechanisms of CRPC resistance include androgen receptor (AR) splice variants, mutations, and de novo androgen synthesis.
- The AR N-terminal domain (NTD) is a key driver of AR transcriptional activity and a potential therapeutic target.
Purpose of the Study:
- To identify novel small molecules targeting AR-NTD transcription activity for CRPC treatment.
- To evaluate the efficacy and mechanism of action of a newly identified compound, QW07.
- To explore QW07's potential as a lead compound for AR-NTD-specific antagonists.
Main Methods:
- Development of a screening system targeting AR-NTD transcription activity.
- Screening of a compound library to identify potential drug candidates.
- In vitro and in vivo functional evaluation and mechanism investigation of QW07.
Main Results:
- QW07 was identified as a novel small molecule compound that directly binds to the AR-NTD.
- QW07 effectively blocked AR-NTD transactivation, co-regulatory protein interactions, and downstream gene expression.
- QW07 demonstrated significant inhibition of prostate cancer cell growth in vitro and regression of CRPC xenografts in vivo.
Conclusions:
- QW07 is a potent and specific AR-NTD antagonist with the ability to inhibit both canonical and variant-mediated AR signaling.
- QW07 exhibits significant anti-tumor activity against CRPC, both in vitro and in vivo.
- QW07 represents a promising lead compound for developing targeted therapies against AR-NTD in CRPC.
