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Wesseler, F, Riege, D, Puthanveedu, M, Halver, J, Müller, E, Bertrand, J, Antonchick, AP 
ORCID: https://orcid.org/0000-0003-0435-9443, Sievers, S, Waldmann, H and Schade, D,
2022.
Probing embryonic development enables the discovery of unique small-molecule bone morphogenetic protein potentiators.
Journal of Medicinal Chemistry.
ISSN 0022-2623
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Abstract
We report on the feasibility to harness embryonic development in vitro for the identification of small-molecule cytokine mimetics and signaling activators. Here, a phenotypic, target-agnostic, high throughput assay is presented that probes bone morphogenetic protein (BMP) signaling during mesodermal patterning of embryonic stem cells. The temporal discrimination of BMP- and transforming growth factor-β (TGFβ)-driven stages of cardiomyogenesis underpins a selective, authentic orchestration of BMP cues that can be recapitulated for the discovery of BMP activator chemotypes. Proof of concept is shown from a chemical screen of 7000 compounds, provides a robust hit validation workflow, and afforded 2,3 disubstituted 4H-chromen-4-ones as potent BMP potentiators with osteogenic efficacy. Mechanistic studies suggest that Chromenone 1 enhances canonical BMP outputs at the expense of TGFβ-Smads in an unprecedented manner. Pharmacophoric features were defined, providing a set of novel chemical probes for various applications in (stem) cell biology, regenerative medicine, and basic research on the BMP pathway.
| Item Type: | Journal article |
|---|---|
| Publication Title: | Journal of Medicinal Chemistry |
| Creators: | Wesseler, F., Riege, D., Puthanveedu, M., Halver, J., Müller, E., Bertrand, J., Antonchick, A.P., Sievers, S., Waldmann, H. and Schade, D. |
| Publisher: | American Chemical Society (ACS) |
| Date: | 2 February 2022 |
| ISSN: | 0022-2623 |
| Identifiers: | Number Type 10.1021/acs.jmedchem.1c01800 DOI 1516136 Other |
| Rights: | Published under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license (https://creativecommons.org/licenses/by-nc-nd/4.0/) |
| Divisions: | Schools > School of Science and Technology |
| Record created by: | Laura Ward |
| Date Added: | 07 Feb 2022 10:21 |
| Last Modified: | 07 Feb 2022 10:21 |
| URI: | https://irep.ntu.ac.uk/id/eprint/45524 |
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