Targeting protein-protein interaction by small molecules

Annu Rev Pharmacol Toxicol. 2014;54:435-56. doi: 10.1146/annurev-pharmtox-011613-140028. Epub 2013 Oct 21.

Abstract

Protein-protein interactions (PPIs) are critical regulatory events in physiology and pathology, and they represent an important target space for pharmacological intervention. However, targeting PPIs with small molecules is challenging owing to the large surface area involved in protein-protein binding and the lack of obvious small-molecule-binding pockets at many protein-protein interfaces. Nonetheless, successful examples of small-molecule modulators of PPIs have been growing in recent years. This article reviews some of the recent advances in the discovery of small-molecule regulators of PPIs that involve key oncogenic proteins. Our discussion focuses on the three key modes of action for these small-molecule modulators: orthosteric inhibition, allosteric regulation, and interfacial binding/stabilization. Understanding the opportunities and challenges of these diverse mechanisms will help guide future efforts in developing small-molecule modulators against PPIs.

Publication types

  • Review

MeSH terms

  • Carrier Proteins / agonists
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Humans
  • Membrane Proteins / agonists
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Models, Molecular
  • Molecular Targeted Therapy*
  • Protein Binding
  • Protein Interaction Domains and Motifs / drug effects*
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / metabolism
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • SOS1 Protein / antagonists & inhibitors
  • SOS1 Protein / genetics
  • SOS1 Protein / metabolism
  • Thyroid Hormones / agonists
  • Thyroid Hormones / genetics
  • Thyroid Hormones / metabolism
  • ras Proteins / antagonists & inhibitors
  • ras Proteins / genetics
  • ras Proteins / metabolism

Substances

  • Carrier Proteins
  • Membrane Proteins
  • SOS1 Protein
  • Thyroid Hormones
  • thyroid hormone-binding proteins
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins c-akt
  • ras Proteins