Zebrafish Aid Drug Development

One of the first structure-activity relationship studies in vertebrates confirms that the method can help drug developers zero in on selective small-molecule leads with limited side effects while identifying which leads that look promising in vitro have undesirable in vivo activity (ACS Chem. Biol., DOI: 10.1021/cb9002865). Vanderbilt University’s Charles C. Hong and colleagues performed the study with zebrafish. This tiny fish is an ideal test organism because many experimental drugs can diffuse into its transparent embryo and its development can be monitored for alterations that shed light on a test compound’s bioactivity (C&EN, Sept. 24, 2007, page 103). Hong’s team exposed zebrafish embryos to dorsomorphin, an inhibitor of bone morphogenetic protein (BMP) signaling, which is involved in bone formation and other physiological functions. The assay showed that dorsomorphin also suppresses vascular endothelial growth factor (VEGF) signaling and disrupts angiogenesis. Since both BMP and VEGF are involved in vascular development, the researchers synthesized 63 dorsomorphin analogs to distinguish whether BMP or VEGF affected angiogenesis. DMH1 (shown) inhibited only the BMP pathway and didn’t disrupt angiogenesis, showing that BMP isn’t involved in angiogenesis during development.