Cercosporamide inhibits bone morphogenetic protein receptor type I kinase activity in zebrafish.
Jelmer HoeksmaGerard C M van der ZonPeter Ten DijkeJeroen den HertogPublished in: Disease models & mechanisms (2020)
Zebrafish models are well-established tools for investigating the 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 were strikingly similar to 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 type I BMPRs [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. We believe that cercosporamide could 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.This article has an associated First Person interview with the first author of the paper.
Keyphrases
- pulmonary arterial hypertension
- small molecule
- epithelial mesenchymal transition
- protein kinase
- transforming growth factor
- high glucose
- mesenchymal stem cells
- diabetic rats
- spinal cord
- gene expression
- tyrosine kinase
- cell therapy
- stem cells
- oxidative stress
- spinal cord injury
- risk assessment
- drug induced
- signaling pathway
- protein protein
- advanced non small cell lung cancer