Abstract 1848: Decursin derivatives with increased in vivo stability suppress androgen receptor signaling and prostate cancer cell growth: Structure-bioactivity relationship

Androgen receptor (AR) signaling is crucial for the genesis and progression of prostate cancer (PCa). Targeting AR signaling remains an attractive approach for PCa chemoprevention and therapy. Our previous studies suggest that decursin, which is isolated from the Korean medicinal herb Angelica gigas Nakai, has novel anti-androgen attributes in comparison to that of AR antagonist drug bicalutamide (Casodex) and stronger anti-proliferative and pro-apoptotic activities in cell culture models. However, decursin quickly de-esterifies to decursinol in vivo, which lacks the anti-androgen and anti-proliferative activities. We report here that a novel prototype derivative (decursinol thiocarbamate, DTC) shows in vivo stability in single dose pharmacokinetic studies, with no detection of decursinol. Molecular docking with the wild type AR ligand binding domain (LBD) suggested that its AR-binding energy is inferior to DHT, but higher than decursin. Mechanistically DTC retains all the desirable properties of decursin, including inhibiting AR nuclear translocation, decreasing cellular AR protein abundance by promoting its 26S proteasomal-mediated degradation and lacking agonist activity. Dose-response comparisons showed that DTC was half as potent as decursin to inhibit AR signaling and androgen sensitive LNCaP PCa cell growth. In animal studies with mice, daily i.p. injection of DTC (2 mg per mouse) decreased AR transcriptional targets such as probasin and NKX3.1 in the mouse prostates. Chemical deposits on the surface of liver and other organs were observed suggesting poor solubility. Additional derivatives aimed to improved solubility had been synthesized and are being investigated for structure-activity relationship. Overall, the data suggest that DTC is a prototype stable decursin derivative retaining the novel AR antagonist activity for PCa chemoprevention or treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1848. doi:10.1158/1538-7445.AM2011-1848