The road less traveled: modulating signal transduction enzymes by inhibiting their protein-protein interactions

Curr Opin Chem Biol. 2009 Jun;13(3):284-90. doi: 10.1016/j.cbpa.2009.05.125. Epub 2009 Jun 22.

Abstract

The biological functions of intracellular signaling enzymes typically depend on multiple protein-protein interactions (PPI) with substrates, scaffolding proteins, and other cytoplasmic molecules. Blocking these interactions provides an alternative means to modulate signaling activity without fully ablating the catalytic activity of the target. Several recent reports describe small-molecule antagonists that target PPI sites on signaling enzymes. These findings suggest that such sites may often be druggable. However, the hypothesis that targeting such sites might confer on the resulting inhibitors improved properties of efficacy and/or tolerability, while appealing, remains largely untested.

Publication types

  • Review

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases
  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Animals
  • Calcineurin Inhibitors
  • Cell Cycle Proteins / antagonists & inhibitors
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors
  • Humans
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Models, Molecular
  • NFATC Transcription Factors / antagonists & inhibitors
  • Protein Interaction Domains and Motifs / drug effects
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Signal Transduction / drug effects*

Substances

  • Adaptor Proteins, Signal Transducing
  • Calcineurin Inhibitors
  • Cell Cycle Proteins
  • Enzyme Inhibitors
  • HSP90 Heat-Shock Proteins
  • NFATC Transcription Factors
  • Proto-Oncogene Proteins
  • 3-Phosphoinositide-Dependent Protein Kinases
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1
  • JNK Mitogen-Activated Protein Kinases