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 naturalproduct-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.

Automated summary

Identification of novel bioactive chemical matter can be achieved through target-agnostic cellular assays and monitoring changes in phenotype followed by target identification. In this study, the enantioselective synthesis of natural product-inspired 8-oxotetrahydroprotoberberines led to the identification of Picoberin, a low picomolar inhibitor of Hedgehog-induced osteoblast differentiation. The molecular target of Picoberin was identified as the aryl hydrocarbon receptor (AhR), and a cross talk between Hedgehog and AhR signaling during osteoblast differentiation was revealed.