Development of targeted protein degradation therapeutics

Nat Chem Biol. 2019 Oct;15(10):937-944. doi: 10.1038/s41589-019-0362-y. Epub 2019 Sep 16.


Targeted protein degradation as a therapeutic modality has seen dramatic progress and massive investment in recent years because of the convergence of two key scientific breakthroughs: optimization of first-generation peptidic proteolysis-targeted chimeras (PROTACs) into more drug-like molecules able to support in vivo proof of concept and the discovery that clinical molecules function as degraders by binding and repurposing the proteins cereblon and DCAF15. This provided clinical validation for the general approach through the cereblon modulator class of drugs and provided highly drug-like and ligand-efficient E3 ligase binders upon which to tether target-binding moieties. Increasingly rational and systematic approaches including biophysical and structural studies on ternary complexes are being leveraged as the field advances. In this Perspective we summarize the discoveries that have laid the foundation for future degradation therapeutics, focusing on those classes of small molecules that redirect E3 ubiquitin ligases to non-native substrates.

Publication types

  • Review

MeSH terms

  • Binding Sites
  • Humans
  • Proteasome Endopeptidase Complex
  • Protein Binding
  • Proteolysis / drug effects*
  • Small Molecule Libraries / chemistry
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / metabolism


  • Small Molecule Libraries
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex