Versatile pathway-centric approach based on high-throughput sequencing to anticancer drug discovery

Proc Natl Acad Sci U S A. 2012 Mar 20;109(12):4609-14. doi: 10.1073/pnas.1200305109. Epub 2012 Mar 6.


The advent of powerful genomics technologies has uncovered many fundamental aspects of biology, including the mechanisms of cancer; however, it has not been appropriately matched by the development of global approaches to discover new medicines against human diseases. Here we describe a unique high-throughput screening strategy by high-throughput sequencing, referred to as HTS(2), to meet this challenge. This technology enables large-scale and quantitative analysis of gene matrices associated with specific disease phenotypes, therefore allowing screening for small molecules that can specifically intervene with disease-linked gene-expression events. By initially applying this multitarget strategy to the pressing problem of hormone-refractory prostate cancer, which tends to be accelerated by the current antiandrogen therapy, we identify Peruvoside, a cardiac glycoside, which can potently inhibit both androgen-sensitive and -resistant prostate cancer cells without triggering severe cytotoxicity. We further show that, despite transcriptional reprogramming in prostate cancer cells at different disease stages, the compound can effectively block androgen receptor-dependent gene expression by inducing rapid androgen receptor degradation via the proteasome pathway. These findings establish a genomics-based phenotypic screening approach capable of quickly connecting pathways of phenotypic response to the molecular mechanism of drug action, thus offering a unique pathway-centric strategy for drug discovery.

Publication types

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

MeSH terms

  • Androgens / chemistry
  • Antigens / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Cardenolides / pharmacology
  • Cell Line, Tumor
  • Chemistry, Pharmaceutical / methods
  • Drug Design
  • Drug Screening Assays, Antitumor / methods*
  • Genomics
  • Glycosides / chemistry
  • Humans
  • Phenotype
  • Proteasome Endopeptidase Complex / chemistry
  • RNA Interference


  • Androgens
  • Antigens
  • Antineoplastic Agents
  • Cardenolides
  • Glycosides
  • cannogenin thevetoside
  • Proteasome Endopeptidase Complex

Associated data

  • GEO/GSE35126