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Updated: Dec 8, 2025
Author Spotlight: Evaluating Biophysical Assays for Characterizing PROTACS Ternary Complexes
Published on: January 12, 2024
Design and characterization of cereblon-mediated androgen receptor proteolysis-targeting chimeras
Akshay D Takwale1, Seung-Hyun Jo2, Yeong Uk Jeon3
1Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 305-606, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, Korea University of Science and Technology, Daejeon, 34113, Republic of Korea.
Abstract:
Proteolysis-targeting chimera (PROTAC)-mediated protein degradation is a rapidly emerging therapeutic intervention that induces the degradation of targeted proteins. Herein, we report the design and biological evaluation of a series of androgen receptor (AR) PROTAC degraders for the treatment of metastatic castration-resistant prostate cancer. Predominantly, instead of thalidomide, we utilized the TD-106 scaffold, a novel cereblon (CRBN) binder that was identified in our previous study. Our results suggest that the linker position in the TD-106 CRBN binder is critical for the efficiency of AR degradation. The compounds attached to the 6-position of TD-106 promoted better degradation of AR than those at the 5- and 7-positions. Among the synthesized AR PROTACs, the representative degrader 33c (TD-802) effectively induced AR protein degradation, with a degradation concentration 50% of 12.5 nM and a maximum degradation of 93% in LNCaP prostate cancer cells. Additionally, most AR PROTAC degraders, including TD-802, displayed good liver microsomal stability and in vivo pharmacokinetic properties. Finally, we showed that TD-802 effectively inhibited tumor growth in an in vivo xenograft study.
Insights
New Proteolysis-targeting chimeras (PROTACs) targeting the androgen receptor (AR) show promise for prostate cancer. A novel TD-106 scaffold demonstrated efficient AR degradation and tumor growth inhibition in preclinical models.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Pharmacology
Background:
- Proteolysis-targeting chimera (PROTAC)-mediated protein degradation is an emerging therapeutic strategy.
- Androgen receptor (AR) signaling is a key driver in prostate cancer progression, particularly metastatic castration-resistant prostate cancer (mCRPC).
- Novel cereblon (CRBN) binders are needed to develop effective PROTACs.
Purpose of the Study:
- To design and biologically evaluate novel AR PROTAC degraders for mCRPC treatment.
- To investigate the impact of linker position on AR degradation efficiency using the TD-106 CRBN binder scaffold.
- To assess the preclinical efficacy of lead AR PROTAC degraders in vitro and in vivo.
Main Methods:
- Synthesis and chemical modification of AR PROTACs utilizing the TD-106 CRBN binder.
- Evaluation of AR protein degradation in LNCaP prostate cancer cells.
- Assessment of liver microsomal stability, pharmacokinetic properties, and in vivo efficacy in xenograft models.
Main Results:
- Linker attachment at the 6-position of the TD-106 scaffold significantly enhanced AR degradation compared to 5- and 7-positions.
- The representative degrader TD-802 (compound 33c) achieved potent AR degradation (DC50 = 12.5 nM, 93% max degradation) in LNCaP cells.
- TD-802 exhibited favorable metabolic stability, pharmacokinetic profiles, and demonstrated significant tumor growth inhibition in vivo.
Conclusions:
- The TD-106 scaffold is a viable alternative to thalidomide for developing potent AR PROTACs.
- Optimized linker positioning is crucial for efficient AR degradation mediated by TD-106 based PROTACs.
- TD-802 represents a promising therapeutic candidate for metastatic castration-resistant prostate cancer.
