Small-molecule inhibitors of protein-protein interactions: progressing toward the reality

Chem Biol. 2014 Sep 18;21(9):1102-14. doi: 10.1016/j.chembiol.2014.09.001.

Abstract

The past 20 years have seen many advances in our understanding of protein-protein interactions (PPIs) and how to target them with small-molecule therapeutics. In 2004, we reviewed some early successes; since then, potent inhibitors have been developed for diverse protein complexes, and compounds are now in clinical trials for six targets. Surprisingly, many of these PPI clinical candidates have efficiency metrics typical of "lead-like" or "drug-like" molecules and are orally available. Successful discovery efforts have integrated multiple disciplines and make use of all the modern tools of target-based discovery-structure, computation, screening, and biomarkers. PPIs become progressively more challenging as the interfaces become more complex, i.e., as binding epitopes are displayed on primary, secondary, or tertiary structures. Here, we review the last 10 years of progress, focusing on the properties of PPI inhibitors that have advanced to clinical trials and prospects for the future of PPI drug discovery.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Allosteric Regulation / drug effects
  • Apoptosis Regulatory Proteins / antagonists & inhibitors
  • Apoptosis Regulatory Proteins / metabolism
  • Binding Sites
  • HIV Integrase / chemistry
  • HIV Integrase / metabolism
  • Humans
  • Peptides / chemistry
  • Peptides / metabolism
  • Protein Interaction Domains and Motifs / drug effects
  • Protein Interaction Maps / drug effects
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Proteins / antagonists & inhibitors*
  • Proteins / metabolism
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / metabolism
  • Small Molecule Libraries / pharmacology

Substances

  • Apoptosis Regulatory Proteins
  • Peptides
  • Proteins
  • Small Molecule Libraries
  • HIV Integrase