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.

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.

• Authors: Ya-Ming Xu, Manping X Liu, Nathan Grunow, E M Kithsiri Wijeratne, Gillian Paine-Murrieta, Stephen Felder, Richard M Kris, A A Leslie Gunatilaka
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 17 Pg. 6984-93 (Sep 10 2015) ISSN: 1520-4804 [Electronic] United States
• PMID: 26305181 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Androgens
• Antineoplastic Agents
• Biological Products
• Proto-Oncogene Proteins c-ets
• Receptors, Androgen
• SPDEF protein, human
• Withanolides
• physachenolide C
• KLK2 protein, human
• KLK3 protein, human
• Kallikreins
• Prostate-Specific Antigen

Topics

• Androgens (metabolism)
• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Biological Products (chemistry)
• Cell Line, Tumor
• Drug Screening Assays, Antitumor
• Gene Expression (drug effects)
• Gene Expression Profiling
• Heterografts
• High-Throughput Screening Assays
• Humans
• Kallikreins (genetics, metabolism)
• Male
• Mice, SCID
• Neoplasm Transplantation
• Prostate-Specific Antigen (genetics, metabolism)
• Prostatic Neoplasms, Castration-Resistant (drug therapy)
• Proto-Oncogene Proteins c-ets (genetics, metabolism)
• Receptors, Androgen (metabolism)
• Structure-Activity Relationship
• Withanolides (chemical synthesis, chemistry, pharmacology)