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

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

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

Nobumichi Ohoka et al. ACS Chem Biol. .


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.

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