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; A A Leslie Gunatilaka

doi:10.1021/acs.jmedchem.5b00867

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. Epub 2015 Aug 31.

Authors

Ya-Ming Xu¹, Manping X Liu¹, Nathan Grunow², E M Kithsiri Wijeratne¹, Gillian Paine-Murrieta³, Stephen Felder², Richard M Kris², A A Leslie Gunatilaka¹

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Androgens / metabolism*
Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / 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
Kallikreins / metabolism
Male
Mice, SCID
Neoplasm Transplantation
Prostate-Specific Antigen / genetics
Prostate-Specific Antigen / metabolism
Prostatic Neoplasms, Castration-Resistant / drug therapy*
Proto-Oncogene Proteins c-ets / genetics
Proto-Oncogene Proteins c-ets / metabolism
Receptors, Androgen / metabolism
Structure-Activity Relationship
Withanolides / chemical synthesis
Withanolides / chemistry*
Withanolides / pharmacology

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding