Discovery of Potent 17尾-Hydroxywithanolides for Castration-Resistant Prostate Cancer by High-Throughput Screening of a Natural Products Library for Androgen-Induced Gene Expression Inhibitors

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• 作者：Ya-Ming Xu ; Manping X. Liu ; Nathan Grunow ; E. M. Kithsiri Wijeratne ; Gillian Paine-Murrieta ; Stephen Felder ; Richard M. Kris ; A. A. Leslie Gunatilaka
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：September 10, 2015
• 年：2015
• 卷：58
• 期：17
• 页码：6984-6993
• 全文大小：396K
• ISSN：1520-4804

文摘

Prostate cancer (PC) is the second most prevalent cancer among men in Western societies, and those who develop metastatic castration-resistant PC (CRPC) invariably succumb to the disease. The need for effective treatments for CRPC is a pressing concern, especially due to limited durable responses with currently employed therapies. Here, we demonstrate the successful application of a high-throughput gene-expression profiling assay directly targeting genes of the androgen receptor pathway to screen a natural products library leading to the identification of 17尾-hydroxywithanolides 1鈥?b>5, of which physachenolide D (5) exhibited potent and selective in vitro activity against two PC cell lines, LNCaP and PC-3. Epoxidation of 5 afforded physachenolide C (6) with higher potency and stability. Structure鈥揳ctivity relationships for withanolides as potential anti-PC agents are presented together with in vivo efficacy studies on compound 6, suggesting that 17尾-hydroxywithanolides are promising candidates for further development as CRPC therapeutics.