Comparative assessment of the effects of bumped kinase inhibitors on early zebrafish embryo development and pregnancy in mice
2020
Anghel, Nicoleta | Winzer, Pablo A. | Imhof, Dennis | Müller, Joachim | Langa, Xavier | Rieder, Jessica | Barrett, Lynn K. | Vidadala, Rama Subba Rao | Huang, Wenlin | Choi, Ryan | Hulverson, Mathew A. | Whitman, Grant R. | Arnold, Samuel L. | Van Voorhis, Wesley C. | Ojo, Kayode K. | Maly, Dustin J. | Fan, Erkang | Hemphill, Andrew
Bumped kinase inhibitors (BKIs) are effective against a variety of apicomplexan parasites. Fifteen BKIs with promising in vitro efficacy against Neospora caninum tachyzoites, low cytotoxicity in mammalian cells, and no toxic effects in non-pregnant BALB/c mice were assessed in pregnant mice. Drugs were emulsified in corn oil and were applied by gavage for 5 days. Five BKIs did not affect pregnancy, five BKIs exhibited ~15–35% neonatal mortality and five compounds caused strong effects (infertility, abortion, stillbirth and pup mortality). Additionally, the impact of these compounds on zebrafish (Danio rerio) embryo development was assessed by exposing freshly fertilised eggs to 0.2–50 μM of BKIs and microscopic monitoring of embryo development in a blinded manner for 4 days. We propose an algorithm that includes quantification of malformations and embryo deaths, and established a scoring system that allows the calculation of an impact score (Sᵢ) indicating at which concentrations BKIs visibly affect zebrafish embryo development. Comparison of the two models showed that for nine compounds no clear correlation between Sᵢ and pregnancy outcome was observed. However, the three BKIs affecting zebrafish embryos only at high concentrations (≥40 μM) did not impair mouse pregnancy at all, and the three compounds that inhibited zebrafish embryo development already at 0.2 μM showed detrimental effects in the pregnancy model. Thus, the zebrafish embryo development test has limited predictive value to foresee pregnancy outcome in BKI-treated mice. We conclude that maternal health-related factors such as cardiovascular, pharmacokinetic and/or bioavailability properties also contribute to BKI–pregnancy effects.
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