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Updated: Oct 20, 2025
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Development of a Benzothiazole Scaffold-Based Androgen Receptor N-Terminal Inhibitor for Treating Androgen-Responsive
Nane C Kuznik1, Valeria Solozobova1, Nicole Jung2
1Institute of Biological and Chemical Systems, Biological Information Processing, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany.
Abstract:
All current clinically approved androgen deprivation therapies for prostate cancer target the C-terminal ligand-binding domain of the androgen receptor (AR). However, the main transactivation function of the receptor is localized at the AR N-terminal domain (NTD). Targeting the AR NTD directly is a challenge because of its intrinsically disordered structure and the lack of pockets for drugs to bind. Here, we have taken an alternative approach using the cochaperone BAG1L, which interacts with the NTD, to develop a novel AR inhibitor. We describe the identification of 2-(4-fluorophenyl)-5-(trifluoromethyl)-1,3-benzothiazole (A4B17), a small molecule that inhibits BAG1L-AR NTD interaction, attenuates BAG1L-mediated AR NTD activity, downregulates AR target gene expression, and inhibits proliferation of AR-positive prostate cancer cells. This compound represents a prototype of AR antagonists that could be key in the development of future prostate cancer therapeutics.
Insights
Researchers developed a novel prostate cancer therapy targeting the androgen receptor (AR) N-terminal domain (NTD) by inhibiting the BAG1L-AR NTD interaction. This new approach offers a promising strategy for future AR-targeted prostate cancer treatments.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Current androgen deprivation therapies target the AR C-terminal domain.
- The AR N-terminal domain (NTD) is crucial for transactivation but difficult to target directly due to its disordered structure.
- The cochaperone BAG1L interacts with the AR NTD, presenting a potential therapeutic target.
Purpose of the Study:
- To develop a novel androgen receptor (AR) inhibitor by targeting the AR NTD via its interaction with the cochaperone BAG1L.
- To identify small molecules that disrupt the BAG1L-AR NTD interaction.
- To evaluate the efficacy of identified compounds in inhibiting AR activity and prostate cancer cell proliferation.
Main Methods:
- Screening for small molecules that inhibit the BAG1L-AR NTD interaction.
- Characterization of the identified compound 2-(4-fluorophenyl)-5-(trifluoromethyl)-1,3-benzothiazole (A4B17).
- Assessment of A4B17's effects on AR NTD activity, AR target gene expression, and prostate cancer cell proliferation.
Main Results:
- Identification of A4B17, a small molecule that inhibits BAG1L-AR NTD interaction.
- A4B17 attenuates BAG1L-mediated AR NTD activity and downregulates AR target gene expression.
- A4B17 inhibits the proliferation of AR-positive prostate cancer cells.
Conclusions:
- A4B17 is a novel AR antagonist targeting the AR NTD through inhibition of the BAG1L interaction.
- This approach represents a new strategy for developing therapeutics against AR-positive prostate cancer.
- The identified compound serves as a prototype for future AR-targeted prostate cancer treatments.
