Exploring the mode-of-action of bioactive compounds by chemical-genetic profiling in yeast

Cell. 2006 Aug 11;126(3):611-25. doi: 10.1016/j.cell.2006.06.040.


Discovering target and off-target effects of specific compounds is critical to drug discovery and development. We generated a compendium of "chemical-genetic interaction" profiles by testing the collection of viable yeast haploid deletion mutants for hypersensitivity to 82 compounds and natural product extracts. To cluster compounds with a similar mode-of-action and to reveal insights into the cellular pathways and proteins affected, we applied both a hierarchical clustering and a factorgram method, which allows a gene or compound to be associated with more than one group. In particular, tamoxifen, a breast cancer therapeutic, was found to disrupt calcium homeostasis and phosphatidylserine (PS) was recognized as a target for papuamide B, a cytotoxic lipopeptide with anti-HIV activity. Further, the profile of crude extracts resembled that of its constituent purified natural product, enabling detailed classification of extract activity prior to purification. This compendium should serve as a valuable key for interpreting cellular effects of novel compounds with similar activities.

Publication types

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

MeSH terms

  • Antineoplastic Agents, Hormonal / pharmacology
  • Antiviral Agents / pharmacology
  • Cluster Analysis
  • Depsipeptides / pharmacology
  • Drug Evaluation, Preclinical / methods*
  • Drug Resistance / genetics*
  • Fungal Proteins / drug effects
  • Fungal Proteins / genetics
  • Fungal Proteins / metabolism
  • Gene Expression Profiling / methods*
  • Molecular Structure
  • Mutation / drug effects
  • Mutation / genetics
  • Pharmaceutical Preparations / chemistry
  • Pharmaceutical Preparations / classification
  • Pharmaceutical Preparations / metabolism*
  • Phosphatidylserines / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Tamoxifen / pharmacology
  • Yeasts / drug effects*
  • Yeasts / genetics*
  • Yeasts / metabolism


  • Antineoplastic Agents, Hormonal
  • Antiviral Agents
  • Depsipeptides
  • Fungal Proteins
  • Pharmaceutical Preparations
  • Phosphatidylserines
  • papuamide B
  • Tamoxifen