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

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.