Development of Small Molecule Chimeras That Recruit AhR E3 Ligase to Target Proteins

ACS Chem Biol. 2019 Dec 20;14(12):2822-2832. doi: 10.1021/acschembio.9b00704. Epub 2019 Oct 16.


Targeted protein degradation using chimeric small molecules such as proteolysis-targeting chimeras (PROTACs) and specific and nongenetic inhibitors of apoptosis protein [IAP]-dependent protein erasers (SNIPERs) is an emerging modality in drug discovery. Here, we expand the repertoire of E3 ligases capable of ubiquitylating target proteins using this system. By incorporating β-naphthoflavone (β-NF) as a ligand, we developed a novel class of chimeric molecules that recruit the arylhydrocarbon receptor (AhR) E3 ligase complex. β-NF-ATRA, a chimeric degrader directed against cellular retinoic acid binding proteins (CRABPs), induced the AhR-dependent degradation of CRABP-1 and CRABP-2 via the ubiquitin-proteasome pathway. A similar compound ITE-ATRA, in which an alternative AhR ligand was used, also degraded CRABP proteins. Finally, we developed a chimeric compound β-NF-JQ1 that is directed against bromodomain-containing (BRD) proteins using β-NF as an AhR ligand. β-NF-JQ1 induced the interaction of AhR and BRD proteins and displayed effective anticancer activity that correlated with protein knockdown activity. These results demonstrate a novel class of chimeric degrader molecules based on the ability to bring a target protein and an AhR E3 ligase into close proximity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Female
  • Humans
  • Inhibitor of Apoptosis Proteins / antagonists & inhibitors
  • Ligands
  • MCF-7 Cells
  • Receptors, Aryl Hydrocarbon / metabolism*
  • Receptors, Retinoic Acid / metabolism
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Ubiquitin-Protein Ligases / metabolism*


  • Inhibitor of Apoptosis Proteins
  • Ligands
  • Receptors, Aryl Hydrocarbon
  • Receptors, Retinoic Acid
  • Small Molecule Libraries
  • Ubiquitin-Protein Ligases