Tricyclic Diterpenoids Selectively Suppress Androgen Receptor-Positive Prostate Cancer Cells

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Androgen receptor (AR) signaling drives castration-resistant prostate cancer (CRPC) progression.
• Current AR antagonists targeting the ligand-binding domain (LBD) are limited by resistance mechanisms in CRPC.
• AR N-terminal antagonists offer a potential alternative therapeutic strategy.

Purpose of the Study:

• To explore the structure-activity relationship of tricyclic diterpenoids as AR antagonists.
• To evaluate the antiproliferative potential of novel diterpenoids against AR-positive prostate cancer cells.
• To identify potent and selective AR-targeting compounds for CRPC treatment.

Main Methods:

• Synthesis and preparation of twenty tricyclic diterpenoids based on the QW07 scaffold.
• Antiproliferative assays using AR-positive (LNCaP, 22Rv1) and AR-null (PC-3, DU145) prostate cancer cell lines.
• Comparison of diterpenoid potency against enzalutamide and QW07.

Main Results:

• Six synthesized tricyclic diterpenoids demonstrated superior potency compared to enzalutamide in AR-positive LNCaP and 22Rv1 cells.
• Four diterpenoids exhibited greater potency than enzalutamide specifically against 22Rv1 cells.
• The lead derivative showed enhanced potency (IC50 = 0.27 µM) and selectivity over QW07 against AR-positive 22Rv1 cells.

Conclusions:

• Tricyclic diterpenoids represent a promising class of compounds for targeting AR in CRPC.
• Optimized diterpenoid derivatives can overcome resistance mechanisms associated with current AR antagonists.
• Further development of these N-terminal AR antagonists holds potential for improved CRPC therapy.