Chemical Genetics Reveals a Role of dCTP Pyrophosphatase 1 in Wnt Signaling

• Published in: Angewandte Chemie International Edition 2019-09, Vol.58 (37), p.13009-13013
• Main Authors: Friese, Alexandra, Kapoor, Shobhna, Schneidewind, Tabea, Vidadala, Srinivasa Rao, Sardana, Juhi, Brause, Alexandra, Förster, Tim, Bischoff, Matthias, Wagner, Jessica, Janning, Petra, Ziegler, Slava, Waldmann, Herbert
• Format: Article
• Language: English
• Subjects: Biological activity; Carcinogenesis; Carcinogens; Deregulation; Embryogenesis; Embryonic growth stage; Embryos; Genetics; Homeostasis; Hydrolase; Inhibitors; Modulators; natural products; Organic chemistry; protein-protein interactions; Pyrophosphatase; Regulators; Signal monitoring; Signal transduction; Signaling; small-molecule inhibitors; target identification; Target recognition; Ubiquitin; Wnt pathway; Wnt protein
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201905977

Cell‐based screening is a powerful approach to identify novel chemical modulators and biological components of relevant biological processes. The canonical Wnt pathway is essential for normal embryonic development and tissue homeostasis, and its deregulation plays a crucial role in carcinogenesis. Therefore, the identification of new pathway members and regulators is of significant interest. By means of a cell‐based assay monitoring Wnt signaling we identified the pyrrolocoumarin Pyrcoumin as inhibitor of canonical Wnt signaling. Target identification and validation revealed that Pyrcoumin is a competitive inhibitor of dCTP pyrophosphatase 1 (dCTPP1). We demonstrate a yet unknown interaction of dCTPP1 with ubiquitin carboxyl‐terminal hydrolase (USP7) that is counteracted by dCTPP1 inhibitors. These findings indicate that dCTPP1 plays a role in regulation of Wnt/β‐catenin signaling most likely through a direct interaction with USP7. A cell‐based screening for inhibitors of canonical Wnt signaling identified the pyrrolocoumarin Pyrcoumin, a new competitive inhibitor of dCTP pyrophosphatase 1 (dCTPP1). Pyrcoumin counteracts the previously unknown interaction of dCTPP1 with ubiquitin carboxyl‐terminal hydrolase (USP7).