Scientists at Vanderbilt University have previously used zebrafish embryos to identify compounds that interfere with signalling pathways involved in early development – pathways that also play a role in many disease processes. One of these compounds, dorsomorphin, was shown to block bone morphogenetic protein (BMP) signalling, a pathway that is involved in bone and cartilage formation and that has also been linked to anaemia and inflammatory responses. Subsequent studies showed that dorsomorphin also blocked the vascular endothelial growth factor (VEGF) type-2 receptor and disrupted angiogenesis.
To identify more selective compounds, the team turned again to zebrafish embryos. It was quickly discovered that the two effects could be separated, with some compounds only affecting patterning and some only affecting angiogenesis. The former were shown to be potent and selective inhibitors of BMP signalling and the latter to be selective VEGF inhibitors. As well as identifying a VEGF inhibitor that outperformed a compound that had entered phase III clinical trials, the team also discovered a BMP inhibitor, DMH1, which exclusively targets the BMP pathway. Using zebrafish embryos for structure-activity analyses allows selectivity and bioavailability to be assessed at the same time as efficacy and the team believe that zebrafish provide an attractive complementary platform for drug discovery. The potential of small molecule signalling inhibitors is often limited by off-target activities and zebrafish provide a very good model for assessing selectivity since compounds that hit multiple targets are toxic to the embryos.
The study is published in ACS Chemical Biology.