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Updated: Aug 7, 2025
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Targeting androgen receptor and the variants by an orally bioavailable Proteolysis Targeting Chimeras compound in
Chiu-Lien Hung1, Hao-Hsuan Liu1, Chih-Wei Fu1
1Department of Preclinical Drug Discovery Technology, Biomedical Technology and Devices Research Labs, Industrial Technology Research Institute, Hsinchu 31040, Taiwan.
Background:
Despite the advent of improved therapeutic options for advanced prostate cancer, the durability of clinical benefits is limited due to inevitable development of resistance. By constitutively sustaining androgen receptor (AR) signaling, expression of ligand-binding domain truncated AR variants (AR-V(ΔLBD)) accounts for the major mechanism underlying the resistance to anti-androgen drugs. Strategies to target AR and its LBD truncated variants are needed to prevent the emergence or overcome drug resistance.
Methods:
We utilize Proteolysis Targeting Chimeras (PROTAC) technology to achieve induced degradation of both full-length AR (AR-FL) and AR-V(ΔLBD) proteins. In the ITRI-PROTAC design, an AR N-terminal domain (NTD) binding moiety is appended to von-Hippel-Lindau (VHL) or Cereblon (CRBN) E3 ligase binding ligand with linker.
Findings:
In vitro studies demonstrate that ITRI-PROTAC compounds mechanistically degrade AR-FL and AR-V(ΔLBD) proteins via ubiquitin-proteasome system, leading to impaired AR transactivation on target gene expression, and inhibited cell proliferation accompanied by apoptosis activation. The compounds also significantly inhibit enzalutamide-resistant growth of castration resistant prostate cancer (CRPC) cells. In castration-, enzalutamide-resistant CWR22Rv1 xenograft model without hormone ablation, ITRI-90 displays a pharmacokinetic profile with decent oral bioavailability and strong antitumor efficacy.
Interpretation:
AR NTD that governs the transcriptional activities of all active variants has been considered attractive therapeutic target to block AR signaling in prostate cancer cells. We demonstrated that utilizing PROTAC for induced AR protein degradation via NTD represents an efficient alternative therapeutic strategy for CRPC to overcome anti-androgen resistance.
Funding:
The funding detail can be found in the Acknowledgements section.
Insights
New PROTACs degrade both full-length androgen receptor (AR) and AR variants, overcoming resistance in advanced prostate cancer. This targeted protein degradation offers a promising strategy against anti-androgen drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Advanced prostate cancer treatments face limited durability due to drug resistance.
- Resistance is often driven by truncated Androgen Receptor variants (AR-V(ΔLBD)) that sustain signaling.
- Targeting both full-length AR (AR-FL) and AR variants is crucial for overcoming resistance.
Purpose of the Study:
- To develop and evaluate Proteolysis Targeting Chimeras (PROTACs) for induced degradation of AR-FL and AR-V(ΔLBD).
- To assess the efficacy of these PROTACs in preclinical models of anti-androgen resistant prostate cancer.
Main Methods:
- Designed ITRI-PROTAC compounds targeting the Androgen Receptor N-terminal domain (NTD).
- Utilized von-Hippel-Lindau (VHL) or Cereblon (CRBN) E3 ligase recruitment via PROTAC linker.
- Evaluated compound efficacy in vitro (cell proliferation, apoptosis) and in vivo (xenograft model).
Main Results:
- ITRI-PROTACs effectively degraded AR-FL and AR-V(ΔLBD) proteins through the ubiquitin-proteasome system.
- Compounds inhibited AR transactivation, cell proliferation, and induced apoptosis in vitro.
- ITRI-90 demonstrated significant antitumor efficacy and favorable pharmacokinetics in an enzalutamide-resistant xenograft model.
Conclusions:
- Targeting the AR NTD, which controls all active AR variants, is a viable strategy.
- PROTAC-mediated induced degradation of AR via NTD represents an effective approach to overcome anti-androgen resistance in prostate cancer.
- This strategy offers a promising therapeutic alternative for castration-resistant prostate cancer (CRPC).
