Probing Embryonic Development Enables the Discovery of Unique Small-Molecule Bone Morphogenetic Protein Potentiators
| Autor: | Fabian Wesseler, Daniel Riege, Mahesh Puthanveedu, Jonas Halver, Eva Müller, Jessica Bertrand, Andrey P. Antonchick, Sonja Sievers, Herbert Waldmann, Dennis Schade |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Journal of medicinal chemistry. 65(5) |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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