1. Tricyclic Diterpenoids Selectively Suppress Androgen Receptor-Positive Prostate Cancer Cells.
- Author
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Sekhon I, Chen G, Piri K, Shinkawa S, Ashong D, Zhang Q, Wang G, and Chen QH
- Subjects
- Male, Humans, Receptors, Androgen metabolism, Cell Line, Tumor, Androgen Receptor Antagonists pharmacology, Androgen Receptor Antagonists therapeutic use, Prostatic Neoplasms, Castration-Resistant drug therapy, Diterpenes pharmacology, Diterpenes therapeutic use
- Abstract
Androgen receptor (AR) is a viable therapeutic target for lethal castration-resistant prostate cancer (CRPC), because the continued progression of CRPC is mainly driven by the reactivation of AR transcriptional activity. The current FDA-approved AR antagonists binding to ligand binding domain (LBD) become ineffective in CRPC with AR gene amplification, LBD mutation, and the evolution of LBD-truncated AR splice variants. Encouraged by the fact that tricyclic aromatic diterpenoid QW07 has recently been established as a potential N -terminal AR antagonist, this study aims to explore the structure-activity relationship of tricyclic diterpenoids and their potential to suppress AR-positive cell proliferation. Dehydroabietylamine, abietic acid, dehydroabietic acid, and their derivatives were selected, since they have a similar core structure as QW07. Twenty diterpenoids were prepared for the evaluation of their antiproliferative potency on AR-positive prostate cancer cell models (LNCaP and 22Rv1) using AR-null cell models (PC-3 and DU145) as comparisons. Our data indicated that six tricyclic diterpenoids possess greater potency than enzalutamide (FDA-approved AR antagonist) towards LNCaP and 22Rv1 AR-positive cells, and four diterpenoids are more potent than enzalutamide against 22Rv1 AR-positive cells. The optimal derivative possesses greater potency (IC
50 = 0.27 µM) and selectivity than QW07 towards AR-positive 22Rv1 cells.- Published
- 2023
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