The Highly Potent AhR Agonist Picoberin Modulates Hh-Dependent Osteoblast Differentiation

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.