Probing embryonic development enables the discovery of unique small-molecule bone morphogenetic protein potentiators

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

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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:
NumberType
10.1021/acs.jmedchem.1c01800DOI
1516136Other
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: http://irep.ntu.ac.uk/id/eprint/45524

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