机构：[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 and IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, 4200-135 Porto, Portugal浙江省肿瘤医院[13]IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, 4200-135 Porto, Portugal.浙江省肿瘤医院
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.
基金：
Max Planck Society
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2022]版：
大类|1 区医学
小类|1 区药物化学
最新[2023]版：
大类|1 区医学
小类|1 区药物化学
第一作者：
第一作者机构：[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.
通讯作者：
通讯机构：[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.
医学