The zebrafish embryo, Hong said, is very good at assessing a compound's selectivity for a certain signaling pathway. Mixed signals from compounds that are not selective (they hit multiple targets) are toxic to the embryo it "shuts down development."
The team identified a VEGF inhibitor, for example, that 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.
"If they (the pharmaceutical company) had tested that compound in zebrafish, they would have quickly learned that it wasn't potent or selective," Hong said.
"Using zebrafish is a novel way to do a structure-activity relationship study" a study that examines a series of analog compounds to determine which is the most selective and most potent, he added.
Traditionally, pharmaceutical companies perform these types of studies in vitro, with isolated proteins or cells. But Hong points out that in vitro studies assess only "one dimension" of the biology. Compounds that have great activity in vitro often fail later because they have poor selectivity or because they do not have chemical properties that make them good drugs (they are not "bioavailable").
"The zebrafish assesses selectivity and bioavailability all at the same time," Hong says. "What the traditional approach takes months to do, the zebrafish does in a day."
Because BMP and VEGF inhibitors have therapeutic potential for a variety of diseases, the investigators will begin to test the drug candidates in mouse models.
Hong praised Vanderbilt leaders for putting into place the drug discovery infrastructure that made the wor
|Contact: Leigh MacMillan|
Vanderbilt University Medical Center