The highly potent AhR agonist picoberin modulates Hh-dependent osteoblast differentiation

Flegel, J, Shaaban, S, Jia, ZJ, Schulte, B, Lian, Y, Krzyzanowski, A, Metz, M, Schneidewind, T, Wesseler, F, Flegel, A, Reich, A, Brause, A, Xue, G, Zhang, M, Dötsch, L, Stender, ID, Hoffmann, J-E, Scheel, R, Janning, P, Rastinejad, F, Schade, D, Strohmann, C, Antonchick, AP ORCID: https://orcid.org/0000-0003-0435-9443, Sievers, S, Moura-Alves, P, Ziegler, S and Waldmann, H, 2022. The highly potent AhR agonist picoberin modulates Hh-dependent osteoblast differentiation. Journal of Medicinal Chemistry, 65 (24), pp. 16268-16289. ISSN 0022-2623

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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.

Item Type:	Journal article
Publication Title:	Journal of Medicinal Chemistry
Creators:	Flegel, J., Shaaban, S., Jia, Z.J., Schulte, B., Lian, Y., Krzyzanowski, A., Metz, M., Schneidewind, T., Wesseler, F., Flegel, A., Reich, A., Brause, A., Xue, G., Zhang, M., Dötsch, L., Stender, I.D., Hoffmann, J.-E., Scheel, R., Janning, P., Rastinejad, F., Schade, D., Strohmann, C., Antonchick, A.P., Sievers, S., Moura-Alves, P., Ziegler, S. and Waldmann, H.
Publisher:	American Chemical Society (ACS)
Date:	22 December 2022
Volume:	65
Number:	24
ISSN:	0022-2623
Identifiers:	Number Type 10.1021/acs.jmedchem.2c00956 DOI 1631731 Other
Rights:	Copyright © 2022 The Authors. Published by American Chemical Society. Open access funded by Max Planck Society.
Divisions:	Schools > School of Science and Technology
Record created by:	Linda Sullivan
Date Added:	11 Jan 2023 10:45
Last Modified:	11 Jan 2023 10:45
URI:	https://irep.ntu.ac.uk/id/eprint/47804

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