The design, synthesis and bioactivity evaluation of novel androgen receptor degraders based on hydrophobic tagging

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Prostate cancer (PCa) often progresses to lethal metastatic castration-resistant prostate cancer (mCRPC).
• Androgen receptor (AR)-dependent transcription drives prostate tumor cell growth.
• Targeting AR is crucial for mCRPC treatment.

Purpose of the Study:

• To design, synthesize, and evaluate novel Proteolysis-Targeting Chimaera (PROTAC) based on Hydrophobic Tagging (HyT) for AR degradation.
• To investigate the efficacy of these PROTAC-HyT AR degraders in inhibiting prostate cancer cell proliferation.

Main Methods:

• Synthesis of PROTAC-HyT compounds linking AR antagonists (RU59063) with adamantane-based hydrophobic moieties via alkyl chains.
• Evaluation of AR protein degradation activity in prostate cancer cells.
• Assessment of cell proliferation inhibition using IC50 values.

Main Results:

• Compound D-4-6 demonstrated significant AR protein degradation (57% at 5 μM, ~90% at 20 μM in 24h).
• D-4-6 inhibited LNCaP cell proliferation with an IC50 of 4.77 ± 0.26 μM in a time- and concentration-dependent manner.
• The study established a foundation for developing new mCRPC therapeutics.

Conclusions:

• PROTAC-HyT technology offers a promising strategy for targeting AR in mCRPC.
• Compound D-4-6 shows potent AR degradation and anti-proliferative effects.
• Further optimization of AR-targeting degraders is underway for enhanced therapeutic potential.