The Highly Potent AhR Agonist Picoberin Modulates Hh-Dependent Osteoblast Differentiation PMID: 36459434

ADC Targets in Oncology

2026-04-10

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

J Med Chem. 2022 Dec 22;65(24):16268-16289. doi: 10.1021/acs.jmedchem.2c00956.

Jana Flegel ¹ ² , Saad Shaaban ¹ ³ , Zhi Jun Jia ¹ ⁴ , Britta Schulte ¹ ² , Yilong Lian ⁵ , Adrian Krzyzanowski ¹ ² , Malte Metz ¹ , Tabea Schneidewind ¹ ² , Fabian Wesseler ¹ ² , Anke Flegel ¹ , Alisa Reich ¹ , Alexandra Brause ¹ , Gang Xue ¹ , Minghao Zhang ⁶ , Lara Dötsch ¹ ² , Isabelle D Stender ⁷ , Jan-Erik Hoffmann ⁷ , Rebecca Scheel ⁸ , Petra Janning ¹ , Fraydoon Rastinejad ⁶ , Dennis Schade ⁹ , Carsten Strohmann ⁸ , Andrey P Antonchick ¹ ² ¹⁰ , Sonja Sievers ¹ ¹¹ , Pedro Moura-Alves ⁵ ¹² ¹³ , Slava Ziegler ¹ , Herbert Waldmann ¹ ²

Affiliations

1. Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund 44227, Germany.
2. Faculty of Chemistry, Chemical Biology, Technical University Dortmund, Dortmund 44227, Germany.
3. Faculty of Chemistry, Institute of Organic Chemistry, University of Vienna Währinger Str. 38, Vienna 1090, Austria.
4. Key Laboratory of Birth Defects and Related Diseases of Women and Children, Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu 610041, China.
5. Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.
6. Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford, OX3 7FZ, UK.
7. Protein Chemistry Facility, Max Planck Institute of Molecular Physiology, Dortmund 44227, Germany.
8. Faculty of Chemistry, Inorganic Chemistry, Technical University Dortmund, Dortmund 44227, Germany.
9. Dept. of Pharmaceutical & Medicinal Chemistry, Institute of Pharmacy, Christian-Albrechts-University of Kiel, Kiel 24118, Germany.
10. Department of Chemistry and Forensics, School of Science and Technology, Nottingham Trent University, Clifton Lane, Nottingham, NG11 8NS, United Kingdom.
11. Compound Management and Screening Center, Dortmund 44227, Germany.
12. i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal.
13. IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, 4200-135 Porto, Portugal.

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.