Discovery of Proteolysis-Targeting Chimera Molecules that Selectively Degrade the IRAK3 Pseudokinase

J Med Chem. 2020 Sep 24;63(18):10460-10473. doi: 10.1021/acs.jmedchem.0c01125. Epub 2020 Sep 14.


We report the first disclosure of IRAK3 degraders in the scientific literature. Taking advantage of an opportune byproduct obtained during our efforts to identify IRAK4 inhibitors, we identified ready-to-use, selective IRAK3 ligands in our compound collection with the required properties for conversion into proteolysis-targeting chimera (PROTAC) degraders. This work culminated with the discovery of PROTAC 23, which we demonstrated to be a potent and selective degrader of IRAK3 after 16 h in THP1 cells. 23 induced proteasome-dependent degradation of IRAK3 and required both CRBN and IRAK3 binding for activity. We conclude that PROTAC 23 constitutes an excellent in vitro tool with which to interrogate the biology of IRAK3.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Humans
  • Interleukin-1 Receptor-Associated Kinases / metabolism*
  • Ligands
  • Phthalimides / chemical synthesis
  • Phthalimides / pharmacology*
  • Proteolysis / drug effects*
  • Pyrroles / chemical synthesis
  • Pyrroles / pharmacology*
  • THP-1 Cells
  • Triazines / chemical synthesis
  • Triazines / pharmacology*
  • Ubiquitin-Protein Ligases / metabolism


  • Adaptor Proteins, Signal Transducing
  • CRBN protein, human
  • Ligands
  • Phthalimides
  • Pyrroles
  • Triazines
  • Ubiquitin-Protein Ligases
  • IRAK3 protein, human
  • Interleukin-1 Receptor-Associated Kinases