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

  • J Med Chem. 2022 Mar 10;65(5):3978-3990. doi: 10.1021/acs.jmedchem.1c01800.
Fabian Wesseler  1  2  3 ,  Daniel Riege  3 ,  Mahesh Puthanveedu  1  4 ,  Jonas Halver  1 ,  Eva Müller  5 ,  Jessica Bertrand  5 ,  Andrey P Antonchick  1  4  6 ,  Sonja Sievers  2  4 ,  Herbert Waldmann  1  4 ,  Dennis Schade  3  4  7
Affiliations
  • 1. Faculty of Chemistry and Chemical Biology, Technical University Dortmund, Otto-Hahn-Strasse 6, 44227 Dortmund, Germany.
  • 2. Compound Management and Screening Center, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
  • 3. Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Christian-Albrechts-University of Kiel, Gutenbergstrasse 76, 24118 Kiel, Germany.
  • 4. Max-Planck-Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
  • 5. Department of Orthopedic Surgery, Otto-von-Guericke University, 39120 Magdeburg, Germany.
  • 6. Department of Chemistry and Forensics, College of Science and Technology, Nottingham Trent University, Clifton Lane, NG11 8NS Nottingham, United Kingdom.
  • 7. Partner Site Kiel, DZHK, German Center for Cardiovascular Research, 24105 Kiel, Germany.
PMID: 35108017 DOI: 10.1021/acs.jmedchem.1c01800
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.

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