Selective inhibition of calcineurin-NFAT signaling by blocking protein-protein interaction with small organic molecules

Proc Natl Acad Sci U S A. 2004 May 18;101(20):7554-9. doi: 10.1073/pnas.0401835101. Epub 2004 May 6.

Abstract

Transient or reversible protein-protein interactions are commonly used to ensure efficient targeting of signaling enzymes to their cellular substrates. These interactions include direct binding to substrate, interaction with an accessory or scaffold protein, and positioning at subcellular locations in proximity to substrates. The existence of specialized targeting mechanisms raises the possibility of designing inhibitors that do not block enzyme activity per se, but rather interfere with targeting of the enzyme to one or more of its substrates within the cell. Here, we identify small organic molecules that specifically block targeting of the protein phosphatase calcineurin to its substrate nuclear factor of activated T cells (NFAT, also termed NFATc) and show that they are effective inhibitors of calcineurin-NFAT signaling.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Calcineurin / metabolism*
  • Calcineurin Inhibitors
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / metabolism*
  • NFATC Transcription Factors
  • Nuclear Proteins*
  • Oligopeptides / metabolism
  • Protein Binding
  • Signal Transduction / physiology*
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / metabolism*

Substances

  • Calcineurin Inhibitors
  • DNA-Binding Proteins
  • NFATC Transcription Factors
  • Nuclear Proteins
  • Oligopeptides
  • Transcription Factors
  • VIVIT peptide
  • Calcineurin