TY - JOUR
T1 - 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
AU - Xu, Ya Ming
AU - Liu, Manping X.
AU - Grunow, Nathan
AU - Wijeratne, E. M.Kithsiri
AU - Paine-Murrieta, Gillian
AU - Felder, Stephen
AU - Kris, Richard M.
AU - Gunatilaka, A. A.Leslie
N1 - Publisher Copyright:
© 2015 American Chemical Society.
PY - 2015/9/10
Y1 - 2015/9/10
N2 - 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.
AB - 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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U2 - 10.1021/acs.jmedchem.5b00867
DO - 10.1021/acs.jmedchem.5b00867
M3 - Article
C2 - 26305181
AN - SCOPUS:84941585577
SN - 0022-2623
VL - 58
SP - 6984
EP - 6993
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 17
ER -