The Highly Potent AhR Agonist Picoberin Modulates Hh-Dependent Osteoblast Differentiation.
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
22 12 2022
22 12 2022
Historique:
pubmed:
3
12
2022
medline:
24
12
2022
entrez:
2
12
2022
Statut:
ppublish
Résumé
Identification and analysis of small molecule bioactivity in target-agnostic cellular assays and monitoring changes in phenotype followed by identification of the biological target are a powerful approach for the identification of novel bioactive chemical matter in particular when the monitored phenotype is disease-related and physiologically relevant. Profiling methods that enable the unbiased analysis of compound-perturbed states can suggest mechanisms of action or even targets for bioactive small molecules and may yield novel insights into biology. Here we report the enantioselective synthesis of natural-product-inspired 8-oxotetrahydroprotoberberines and the identification of Picoberin, a low picomolar inhibitor of Hedgehog (Hh)-induced osteoblast differentiation. Global transcriptome and proteome profiling revealed the aryl hydrocarbon receptor (AhR) as the molecular target of this compound and identified a cross talk between Hh and AhR signaling during osteoblast differentiation.
Identifiants
pubmed: 36459434
doi: 10.1021/acs.jmedchem.2c00956
pmc: PMC9791665
doi:
Substances chimiques
Receptors, Aryl Hydrocarbon
0
Hedgehog Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
16268-16289Subventions
Organisme : Wellcome Trust
ID : 210664/Z/18/Z
Pays : United Kingdom
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