Targeted Protein Degradation: from Chemical Biology to Drug Discovery

Cell Chem Biol. 2017 Sep 21;24(9):1181-1190. doi: 10.1016/j.chembiol.2017.05.024. Epub 2017 Jun 22.


Traditional pharmaceutical drug discovery is almost exclusively focused on directly controlling protein activity to cure diseases. Modulators of protein activity, especially inhibitors, are developed and applied at high concentration to achieve maximal effects. Thereby, reduced bioavailability and off-target effects can hamper compound efficacy. Nucleic acid-based strategies that control protein function by affecting expression have emerged as an alternative. However, metabolic stability and broad bioavailability represent development hurdles that remain to be overcome for these approaches. More recently, utilizing the cell's own protein destruction machinery for selective degradation of essential drivers of human disorders has opened up a new and exciting area of drug discovery. Small-molecule-induced proteolysis of selected substrates offers the potential of reaching beyond the limitations of the current pharmaceutical paradigm to expand the druggable target space.

Keywords: E3 ligase; PROTACs; hydrophobic tagging; protein degradation.

Publication types

  • Review

MeSH terms

  • Animals
  • Drug Discovery*
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Proteins / metabolism*
  • Proteolysis / drug effects*
  • Receptors, Estrogen / antagonists & inhibitors
  • Receptors, Estrogen / metabolism
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / metabolism
  • Small Molecule Libraries / pharmacology*
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination / drug effects


  • HSP90 Heat-Shock Proteins
  • Proteins
  • Receptors, Estrogen
  • Small Molecule Libraries
  • Ubiquitin-Protein Ligases