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Abstract 6550: WD105, a novel decursin derivative, showed greater growth inhibition and androgen receptor suppression in LNCaP human prostate cancer cells

Androgen receptor (AR) is a primary target for treatment of prostate cancer (PCa). AR signaling plays a critical function in all stages of PCa. Our previous research demonstrated that decursin and its isomer decursinol angelate, a pair of natural compounds from Angelica gigas Nakai, inhibit AR signaling and suppressed the growth of prostate cancer cells in vitro and in vivo. In this study, we have designed a series of pro-drug conjugates of decursin, based on acid-esterified modification, in order to achieve higher water solubility, stronger cytocidal effect and better AR suppression activity. Twelve novel esterified derivatives of decursin were synthesized from decursinol and characterized by 1H-, 13C-NMR and HR-MS techniques. Among them, WD105 displayed the best solubility. Initial structure-activity relationship (SAR) studies were carried out with a cell growth (CCK8) assay and identified WD105 and WD106 as lead compounds with more potency at suppressing LNCaP cell growth than decursin judged by IC50 value. In addition, both WD105 and WD106 induced caspase-mediated cell apoptosis (48h), evidenced by cleavage of PARP, in a concentration-dependent manner. Furthermore, WD105 decreased the transcriptional activity of AR and androgen-induced expression of PSA better than WD106 and decursin when assessed by Western Blot and ELISA. Taken together, these data suggest that WD105 has greater in vitro activity than decursin as an AR targeting lead compound. Future studies will characterize the PK metrics and, if warranted, determine the in vivo antitumor effect of WD105 on the growth of LNCaP-AR xenografts. Citation Format: Wei Wu, Huaiwei Ding, Huiyong Zhang. WD105, a novel decursin derivative, showed greater growth inhibition and androgen receptor suppression in LNCaP human prostate cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6550.