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

  • J Med Chem. 2015 Sep 10;58(17):6984-93. doi: 10.1021/acs.jmedchem.5b00867.
Ya-Ming Xu  1 ,  Manping X Liu  1 ,  Nathan Grunow  2 ,  E M Kithsiri Wijeratne  1 ,  Gillian Paine-Murrieta  3 ,  Stephen Felder  2 ,  Richard M Kris  2 ,  A A Leslie Gunatilaka  1
Affiliations
  • 1. Natural Products Center, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona , 250 East Valencia Road, Tucson, Arizona 85706, United States.
  • 2. NuvoGen Research LLC , P.O. Box 64326, Tucson, Arizona 85728, United States.
  • 3. University of Arizona Cancer Center , 1515 North Campbell Avenue, Tucson, Arizona 85724, United States.
PMID: 26305181 DOI: 10.1021/acs.jmedchem.5b00867
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.