ZFIN ID: ZDB-PUB-200822-16
Cercosporamide inhibits bone morphogenetic protein receptor type I kinase activity in zebrafish
Hoeksma, J., van der Zon, G.C.M., Ten Dijke, P., den Hertog, J.
Date: 2020
Source: Disease models & mechanisms   13(9): (Journal)
Registered Authors: den Hertog, Jeroen
Keywords: Bone morphogenetic protein, Cercosporamide, Dorsomorphin, Kinase inhibitor, Zebrafish
MeSH Terms:
  • Animals
  • Benzofurans/chemistry
  • Benzofurans/isolation & purification
  • Benzofurans/pharmacology*
  • Biological Assay
  • Bone Morphogenetic Protein Receptors, Type I/antagonists & inhibitors
  • Bone Morphogenetic Protein Receptors, Type I/metabolism*
  • Bone Morphogenetic Proteins/metabolism
  • Embryo, Nonmammalian/drug effects
  • Embryo, Nonmammalian/metabolism
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Protein Kinase Inhibitors/chemistry
  • Protein Kinase Inhibitors/pharmacology
  • Signal Transduction/drug effects
  • Time Factors
  • Zebrafish/embryology
  • Zebrafish/metabolism*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed: 32820031 Full text @ Dis. Model. Mech.
Zebrafish models are well established tools for investigating underlying mechanisms of diseases. Here, we identified cercosporamide, a metabolite from the fungus Ascochyta aquiliqiae, as a potent bone morphogenetic protein receptor (BMPR) type I kinase inhibitor through a zebrafish embryo phenotypic screen. The developmental defects in zebrafish, including lack of the ventral fin induced by cercosporamide was strikingly similar as the phenotypes caused by renowned small molecule BMPR type I kinase inhibitors and inactivating mutations in zebrafish BMPRs. In mammalian cell-based assays, cercosporamide blocked BMP/SMAD-dependent transcriptional reporter activity and BMP-induced SMAD1/5-phosphorylation. Biochemical assays with a panel of purified recombinant kinases demonstrated that cercosporamide directly inhibited kinase activity of BMPRs type I (also called activin receptor-like kinases (ALKs)). In mammalian cells, cercosporamide selectively inhibited constitutively active BMPR type I-induced SMAD1/5 phosphorylation. Importantly, cercosporamide rescued the developmental defects caused by constitutively active Alk2 in zebrafish embryos. Taken together, we believe cercosporamide may be the first of a new class of molecules with potential to be developed further for clinical use against diseases that are causally linked to overactivation of BMPR signaling, including Fibrodysplasia ossificans progressiva and diffuse intrinsic pontine glioma.