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Development of Small Molecule Chimeras That Recruit AhR E3 Ligase to Target Proteins
- Source :
- ACS chemical biology. 14(12)
- Publication Year :
- 2019
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Receptors, Retinoic Acid
Ubiquitin-Protein Ligases
Protein degradation
Ligands
01 natural sciences
Biochemistry
Inhibitor of Apoptosis Proteins
Small Molecule Libraries
03 medical and health sciences
Humans
Receptor
Gene knockdown
biology
010405 organic chemistry
Chemistry
Drug discovery
General Medicine
Ligand (biochemistry)
Small molecule
0104 chemical sciences
Cell biology
Ubiquitin ligase
030104 developmental biology
Receptors, Aryl Hydrocarbon
biology.protein
MCF-7 Cells
Molecular Medicine
Female
Target protein
Subjects
Details
- ISSN :
- 15548937
- Volume :
- 14
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- ACS chemical biology
- Accession number :
- edsair.doi.dedup.....0f158bd73afcd7596818248a93745f34