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School of Pharmacy


Pharmaceutical Sciences


In this report we utilized zebrafish (Danio rerio) embryos in a phenotypical high-content screen (HCS) to identify novel leads in a cancer drug discovery program. We initially validated our HCS model using the flavin adenosine dinucleotide (FAD) containing endoplasmic reticulum (ER) enzyme, endoplasmic reticulum oxidoreductase (ERO1) inhibitor EN460. EN460 showed a dose response effect on the embryos with a dose of 10 μM being significantly lethal during early embryonic development. The HCS campaign which employed a small library identified a promising lead compound, a naphthyl-benzoic acid derivative coined compound 1 which had significant dosage and temporally dependent effects on notochord and muscle development in zebrafish embryos. Screening a 369 kinase member panel we show that compound 1 is a PIM3 kinase inhibitor (IC50 = 4.078 μM) and surprisingly a DAPK1 kinase agonist/activator (EC50 = 39.525 μM). To our knowledge this is the first example of a small molecule activating DAPK1 kinase. We provide a putative model for increased phosphate transfer in the ATP binding domain when compound 1 is virtually docked with DAPK1. Our data indicate that observable phenotypical changes can be used in future zebrafish screens to identify compounds acting via similar molecular signaling pathways.

Source Citation

Geldenhuys WJ, Bergeron SA, Mullins JE, et al. High-content screen using zebrafish (Danio rerio) embryos identifies a novel kinase activator and inhibitor. Bioorganic & Medicinal Chemistry Letters. 2017;27(9):2029-2037. doi:10.1016/j.bmcl.2017.02.068