Gene Expression Signature-Based Chemical Genomic Prediction Identifies a Novel Class of HSP90 Pathway Modulators

Cancer Cell. 2006 Oct;10(4):321-30. doi: 10.1016/j.ccr.2006.09.005. Epub 2006 Sep 28.

Abstract

Although androgen receptor (AR)-mediated signaling is central to prostate cancer, the ability to modulate AR signaling states is limited. Here we establish a chemical genomic approach for discovery and target prediction of modulators of cancer phenotypes, as exemplified by AR signaling. We first identify AR activation inhibitors, including a group of structurally related compounds comprising celastrol, gedunin, and derivatives. To develop an in silico approach for target pathway identification, we apply a gene expression-based analysis that classifies HSP90 inhibitors as having similar activity to celastrol and gedunin. Validating this prediction, we demonstrate that celastrol and gedunin inhibit HSP90 activity and HSP90 clients, including AR. Broadly, this work identifies new modes of HSP90 modulation through a gene expression-based strategy.

Publication types

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

MeSH terms

  • Antibiotics, Antineoplastic / pharmacology
  • Benzoquinones / pharmacology
  • Biomarkers, Tumor / metabolism*
  • Cell Culture Techniques
  • Cell Line
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • ErbB Receptors / metabolism
  • Fusion Proteins, bcr-abl / metabolism
  • Gene Expression / drug effects*
  • Gene Expression Profiling
  • Genome, Human*
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors
  • HSP90 Heat-Shock Proteins / metabolism*
  • Humans
  • Inhibitory Concentration 50
  • Lactams, Macrocyclic / pharmacology
  • Limonins / pharmacology
  • Male
  • Metribolone / pharmacology
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • RNA, Messenger / analysis
  • Receptors, Androgen / metabolism*
  • Reproducibility of Results
  • Triterpenes / pharmacology
  • fms-Like Tyrosine Kinase 3 / metabolism

Substances

  • AR protein, human
  • Antibiotics, Antineoplastic
  • Benzoquinones
  • Biomarkers, Tumor
  • HSP90 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • Limonins
  • RNA, Messenger
  • Receptors, Androgen
  • Triterpenes
  • gedunin
  • Metribolone
  • ErbB Receptors
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3
  • Fusion Proteins, bcr-abl
  • tripterine
  • geldanamycin

Associated data

  • GEO/GSE5258
  • GEO/GSE5505
  • GEO/GSE5508