Wesseler, F., Riege, D., Puthanveedu, M., Halver, J., Müller, E., Bertrand, J., Antonchick, A.P. ORCID: 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
|
Text
1516136_Antonchick.pdf - Published version Download (5MB) | Preview |
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: |
|
||||||
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 |
Actions (login required)
Edit View |
Views
Views per month over past year
Downloads
Downloads per month over past year