The Highly Potent AhR Agonist Picoberin Modulates Hh-Dependent Osteoblast Differentiation
Jana Flegel, Saad Shaaban, Zhi Jun Jia, Britta Schulte, Yilong Lian, Adrian Krzyzanowski, Malte Metz, Tabea Schneidewind, Fabian Wesseler, Anke Flegel, Alisa Reich, Alexandra Brause, Gang Xue, Minghao Zhang, Lara Dötsch, Isabelle D Stender, Jan‐Erik Hoffmann, Rebecca Scheel, Petra Janning, Fraydoon Rastinejad, Dennis Schade, Carsten Strohmann, Andrey P. Antonchick, Sonja Sievers, Pedro Moura‐Alves, Slava Ziegler, Herbert Waldmann
Abstract
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.