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

Ya Ming Xu, Manping X. Liu, Nathan Grunow, E. M Kithsiri Wijeratne, Gillian Paine-Murrieta, Stephen Felder, Richard M. Kris, Leslie Gunatilaka

Research output: Contribution to journalArticle

7 Scopus citations


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 17β-hydroxywithanolides 1-5, 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-activity relationships for withanolides as potential anti-PC agents are presented together with in vivo efficacy studies on compound 6, suggesting that 17β-hydroxywithanolides are promising candidates for further development as CRPC therapeutics.

Original languageEnglish (US)
Pages (from-to)6984-6993
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number17
StatePublished - Sep 10 2015


ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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