Zebrafish make waves in drug development
Fish embryos may seem an unlikely resource for investigators searching for new drug candidates. But a team of Vanderbilt investigators has combined the tools of medicinal chemistry and zebrafish biology to identify compounds that may offer therapeutic leads for bone-related diseases and cancer.
The findings, reported in ACS Chemical Biology, support using zebrafish as a novel platform for drug development.
In 2007, Charles Hong, M.D., Ph.D., and colleagues first described using zebrafish embryos to screen for compounds that interfere with signaling pathways involved in early development – pathways known to play roles in a variety of disease processes.
They discovered the compound “dorsomorphin” and demonstrated that it blocked BMP (bone morphogenetic protein) signaling, which has been implicated in anemia, inflammatory responses and bone-related disorders.
But in examining dorsomorphin further, the investigators found that it had other “off-target” effects – it also blocked the VEGF (vascular endothelial growth factor) receptor and disrupted zebrafish blood vessel development, a process called angiogenesis.
“Off-target effects contribute to side effects and limit the therapeutic potential of small molecule signaling inhibitors,” said Hong, assistant professor of Medicine and Pharmacology.
Now, the investigators have used their zebrafish drug discovery screen as a drug development/optimization tool.
Medicinal chemists Craig Lindsley, Ph.D., and Corey Hopkins, Ph.D., used the dorsomorphin “backbone” as a starting point to synthesize many different analogs – subtly different dorsomorphin-like compounds.
Then Hong and his team tested these compounds for their effects on zebrafish embryonic development. They found that the two effects of dorsomorphin could be separated: some of the new compounds were selective BMP inhibitors and some were selective VEGF inhibitors.
One of the VEGF inhibitors even outperformed an existing VEGF inhibitor that was being developed for cancer therapy (blocking angiogenesis cuts off the “supply lines” for a growing tumor) but was pulled from development during a Phase III trial.