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Updated: Oct 4, 2025
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Design, synthesis, and characterization of PROTACs targeting the androgen receptor in prostate and lung cancer models
Lukas M Gockel1, Vladlena Pfeifer1, Fabian Baltes1
1Department of Pharmaceutical & Cell Biological Chemistry, Pharmaceutical Institute, Bonn, Germany.
Abstract:
Although the androgen receptor (AR) is a validated target for the treatment of prostate cancer, resistance to antiandrogens necessitates the development of new therapeutic modalities. Exploiting the ubiquitin-proteasome system with proteolysis-targeting chimeras (PROTACs) has become a practical approach to degrade specific proteins and thus to extend the portfolio of small molecules used for the treatment of a broader spectrum of diseases. Herein, we present three subgroups of enzalutamide-based PROTACs in which only the exit vector was modified. By recruiting cereblon, we were able to demonstrate the potent degradation of AR in lung cancer cells. Furthermore, the initial evaluation enabled the design of an optimized PROTAC with a rigid linker that degraded AR with a DC50 value in the nanomolar range. These results provide novel AR-directed PROTACs and a clear rationale for further investigating AR involvement in lung cancer models.
Insights
New proteolysis-targeting chimeras (PROTACs) targeting the androgen receptor (AR) show potent degradation in lung cancer cells. This research offers novel therapeutic strategies for AR-driven cancers, addressing antiandrogen resistance.
Area of Science:
- Oncology
- Molecular Biology
- Medicinal Chemistry
Background:
- Androgen receptor (AR) is a key target in prostate cancer treatment.
- Resistance to antiandrogen therapies necessitates novel treatment strategies.
- Proteolysis-targeting chimeras (PROTACs) offer a promising approach to degrade target proteins.
Purpose of the Study:
- To develop novel enzalutamide-based PROTACs for androgen receptor (AR) degradation.
- To evaluate the efficacy of these PROTACs in lung cancer cells.
- To optimize PROTAC design for enhanced AR degradation.
Main Methods:
- Design and synthesis of three subgroups of enzalutamide-based PROTACs with modified exit vectors.
- Utilizing cereblon (CRBN) E3 ligase recruitment for AR degradation.
- Assessment of AR degradation efficacy using DC50 values in lung cancer cell lines.
Main Results:
- Demonstrated potent degradation of AR in lung cancer cells by recruiting cereblon.
- Developed an optimized PROTAC with a rigid linker.
- Achieved nanomolar range DC50 values for AR degradation with the optimized PROTAC.
Conclusions:
- Novel AR-directed PROTACs were successfully designed and synthesized.
- These PROTACs effectively degrade AR in lung cancer cells.
- Provides a strong rationale for exploring AR-targeted PROTACs in lung cancer therapy.
