Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead

Cell Chem Biol. 2018 Jan 18;25(1):78-87.e5. doi: 10.1016/j.chembiol.2017.09.010. Epub 2017 Nov 9.

Abstract

Inhibiting protein function selectively is a major goal of modern drug discovery. Here, we report a previously understudied benefit of small molecule proteolysis-targeting chimeras (PROTACs) that recruit E3 ubiquitin ligases to target proteins for their ubiquitination and subsequent proteasome-mediated degradation. Using promiscuous CRBN- and VHL-recruiting PROTACs that bind >50 kinases, we show that only a subset of bound targets is degraded. The basis of this selectivity relies on protein-protein interactions between the E3 ubiquitin ligase and the target protein, as illustrated by engaged proteins that are not degraded as a result of unstable ternary complexes with PROTAC-recruited E3 ligases. In contrast, weak PROTAC:target protein affinity can be stabilized by high-affinity target:PROTAC:ligase trimer interactions, leading to efficient degradation. This study highlights design guidelines for generating potent PROTACs as well as possibilities for degrading undruggable proteins immune to traditional small-molecule inhibitors.

Keywords: CRBN; MAPK/p38; PROTACs; VHL; chemical biology; protein degradation; protein-protein interactions; proteomics; selective degradation; ternary complex.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Design*
  • Humans
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Proteolysis / drug effects
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Ubiquitin-Protein Ligases / antagonists & inhibitors*
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination / drug effects

Substances

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