Chemical proteomics-based analysis of off-target binding profiles for rosiglitazone and pioglitazone: clues for assessing potential for cardiotoxicity

J Med Chem. 2012 Oct 11;55(19):8260-71. doi: 10.1021/jm301204r. Epub 2012 Sep 28.


Drugs exert desired and undesired effects based on their binding interactions with protein target(s) and off-target(s), providing evidence for drug efficacy and toxicity. Pioglitazone and rosiglitazone possess a common functional core, glitazone, which is considered a privileged scaffold upon which to build a drug selective for a given target--in this case, PPARγ. Herein, we report a retrospective analysis of two variants of the glitazone scaffold, pioglitazone and rosiglitazone, in an effort to identify off-target binding events in the rat heart to explain recently reported cardiovascular risk associated with these drugs. Our results suggest that glitazone has affinity for dehydrogenases, consistent with known binding preferences for related rhodanine cores. Both drugs bound ion channels and modulators, with implications in congestive heart failure, arrhythmia, and peripheral edema. Additional proteins involved in glucose homeostasis, synaptic transduction, and mitochondrial energy production were detected and potentially contribute to drug efficacy and cardiotoxicity.

Publication types

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

MeSH terms

  • Animals
  • Chromatography, Affinity
  • Gluconeogenesis
  • Glycolysis
  • Hypoglycemic Agents / chemistry*
  • Hypoglycemic Agents / toxicity
  • Ion Channels / chemistry
  • Ion Channels / metabolism
  • Lipid Metabolism
  • Mitochondria / physiology
  • Myocardium / chemistry*
  • Myocardium / metabolism
  • Oxidoreductases / metabolism
  • Pioglitazone
  • Protein Binding
  • Proteome / chemistry*
  • Proteome / metabolism
  • Proteomics
  • Rats
  • Rosiglitazone
  • Synaptic Transmission
  • Thiazolidinediones / chemistry*
  • Thiazolidinediones / toxicity


  • Hypoglycemic Agents
  • Ion Channels
  • Proteome
  • Thiazolidinediones
  • Rosiglitazone
  • Oxidoreductases
  • Pioglitazone