Developmental Toxicity Associated with Receptor Tyrosine Kinase Ret Inhibition in Reproductive Toxicity Testing

BACKGROUND: Urogenital abnormalities are among the most common of all human birth defects. In developmental toxicity studies with the Syk kinase inhibitor 8788, a spectrum of findings, including renal agenesis, were observed. 8788 has also been found to inhibit the receptor tyrosine kinase Ret. Ret kinase is known to be an essential component in the signaling pathway required for renal organogenesis and ureteric duct formation. Previously known is that mutant mice without the c-ret gene, develop urogenital malformations including renal agenesis. METHODS: In GLP developmental toxicity studies, gravid rabbits were treated orally with 8788 at doses of 0, 10, 22, and 50 mg/kg/day (gestation days 7-19) and gravid rats received 0, 5, 12.5, and 25 mg/kg/day (gestation days 6-17) by the same route. The activity of 8406 against Ret kinase was assessed in biochemical and cell-based assays. RESULTS: A dose-dependent increase in malformations, including renal and ureteric agenesis and a specific major vessel anomaly, retroesophageal right subclavian artery, was observed in both the rat and rabbit. 8788 proved to be a potent inhibitor of Ret kinase. CONCLUSIONS: 8788 promoted a spectrum of developmental toxicity, including renal and ureteric agenesis and a specific major vessel abnormality, retroesophageal right subclavian artery, in two different species. These effects are likely the result of inhibition of Ret kinase given its importance in the normal ontogeny of the urogenital and cardiovascular systems across species. Birth Defects Research (Part A) 85:130136, 2009. (C) 2008 Wiley-Liss, Inc.