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 Citations (Scopus)

Abstract

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
Volume58
Issue number17
DOIs
StatePublished - Sep 10 2015

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Castration
Biological Products
Androgens
Prostatic Neoplasms
Gene Expression
Withanolides
Gene Targeting
Androgen Receptors
Gene Expression Profiling
Structure-Activity Relationship
Therapeutics
Cell Line
Neoplasms

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

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

In: Journal of Medicinal Chemistry, Vol. 58, No. 17, 10.09.2015, p. 6984-6993.

Research output: Contribution to journalArticle

Xu, Ya Ming ; Liu, Manping X. ; Grunow, Nathan ; Wijeratne, E. M Kithsiri ; Paine-Murrieta, Gillian ; Felder, Stephen ; Kris, Richard M. ; Gunatilaka, Leslie. / 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. In: Journal of Medicinal Chemistry. 2015 ; Vol. 58, No. 17. pp. 6984-6993.
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abstract = "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.",
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