The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study

Cell Chem Biol. 2018 Jan 18;25(1):67-77.e3. doi: 10.1016/j.chembiol.2017.09.009. Epub 2017 Nov 9.

Abstract

Proteolysis targeting chimera (PROTAC) technology has emerged over the last two decades as a powerful tool for targeted degradation of endogenous proteins. Herein we describe the development of PROTACs for receptor tyrosine kinases, a protein family yet to be targeted for induced protein degradation. The use of VHL-recruiting PROTACs against this protein family reveals several advantages of degradation over inhibition alone: direct comparisons of fully functional, target-degrading PROTACs with target-inhibiting variants that contain an inactivated E3 ligase-recruiting ligand show that degradation leads to more potent inhibition of cell proliferation and a more durable and sustained downstream signaling response, and thus addresses the kinome rewiring challenge seen with many receptor tyrosine kinase inhibitors. Combined, these findings demonstrate the ability to target receptor tyrosine kinases for degradation using the PROTAC technology and outline the advantages of this degradation-based approach.

Keywords: EGFR; HER2; PROTAC; VHL; c-Met; receptor tyrosine kinases; targeted degradation.

Publication types

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

MeSH terms

  • Chimera / metabolism
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Ligands
  • Proteolysis / drug effects*
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Ubiquitin-Protein Ligases / antagonists & inhibitors*
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Enzyme Inhibitors
  • Ligands
  • Ubiquitin-Protein Ligases
  • Receptor Protein-Tyrosine Kinases