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Development of Small Molecule Chimeras That Recruit AhR E3 Ligase to Target Proteins
journal contribution
posted on 2019-10-16, 13:37 authored by Nobumichi Ohoka, Genichiro Tsuji, Takuji Shoda, Takuma Fujisato, Masaaki Kurihara, Yosuke Demizu, Mikihiko NaitoTargeted
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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CRABPβ- NF-JQ 1IAPAhR E 3 ligaseITE-ATRAalternative AhR ligandNF-ATRAE 3 ligaseBRDchimeric compound β- NF-JQ 1Target Proteins Targeted protein degradationE 3 ligasesPROTACSmall Molecule Chimerasubiquitylating target proteinsRecruit AhR E 3 Ligaseretinoic acid binding proteinsprotein knockdown activitynovel classchimeric degrader moleculesSNIPER
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