Analysis of Pfizer compounds in EPA's ToxCast chemicals-assay space

Chem Res Toxicol. 2014 Jan 21;27(1):86-98. doi: 10.1021/tx400343t. Epub 2013 Dec 11.


The U.S. Environmental Protection Agency (EPA) launched the ToxCast program in 2007 with the goal of evaluating high-throughput in vitro assays to prioritize chemicals that need toxicity testing. Their goal was to develop predictive bioactivity signatures for toxic compounds using a set of in vitro assays and/or in silico properties. In 2009, Pfizer joined the ToxCast initiative by contributing 52 compounds with preclinical and clinical data for profiling across the multiple assay platforms available. Here, we describe the initial analysis of the Pfizer subset of compounds within the ToxCast chemical (n = 1814) and in vitro assay (n = 486) space. An analysis of the hit rate of Pfizer compounds in the ToxCast assay panel allowed us to focus our mining of assays potentially most relevant to the attrition of our compounds. We compared the bioactivity profile of Pfizer compounds to other compounds in the ToxCast chemical space to gain insights into common toxicity pathways. Additionally, we explored the similarity in the chemical and biological spaces between drug-like compounds and environmental chemicals in ToxCast and compared the in vivo profiles of a subset of failed pharmaceuticals having high similarity in both spaces. We found differences in the chemical and biological spaces of pharmaceuticals compared to environmental chemicals, which may question the applicability of bioactivity signatures developed exclusively based on the latter to drug-like compounds if used without prior validation with the ToxCast Phase-II chemicals. Finally, our analysis has allowed us to identify novel interactions for our compounds in particular with multiple nuclear receptors that were previously not known. This insight may help us to identify potential liabilities with future novel compounds.

MeSH terms

  • Animals
  • Computer Simulation
  • Drug Industry / methods*
  • Drug-Related Side Effects and Adverse Reactions*
  • High-Throughput Screening Assays / methods*
  • Pharmaceutical Preparations / analysis
  • Pharmaceutical Preparations / chemistry
  • Pharmaceutical Preparations / metabolism*
  • Reproducibility of Results
  • Structure-Activity Relationship
  • Toxicity Tests / methods*
  • Toxicology / methods*
  • United States
  • United States Environmental Protection Agency*


  • Pharmaceutical Preparations