Probing Embryonic Development Enables the Discovery of Unique Small-Molecule Bone Morphogenetic Protein Potentiators

• Published in: Journal of medicinal chemistry 2022-03, Vol.65 (5), p.3978-3990
• Main Authors: Wesseler, Fabian, Riege, Daniel, Puthanveedu, Mahesh, Halver, Jonas, Müller, Eva, Bertrand, Jessica, Antonchick, Andrey P, Sievers, Sonja, Waldmann, Herbert, Schade, Dennis
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c01800

We report on the feasibility to harness embryonic development 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 4 -chromen-4-ones as potent BMP potentiators with osteogenic efficacy. Mechanistic studies suggest that Chromenone 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.