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 R788, a spectrum of findings, including renal agenesis, were observed. R788 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 R788 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 R406 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. R788 proved to be a potent inhibitor of Ret kinase.


CONCLUSIONS
R788 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.
Clemens
George R
GR
Rigel Pharmaceuticals, Inc., 1180 Veterans Blvd., South San Francisco, CA 94080, USA. gclemens@rigel.com
Schroeder
Raymond E
RE
Magness
Steven H
SH
Weaver
Elizabeth V
EV
Lech
Joseph W
JW
Taylor
Vanessa C
VC
Masuda
Esteban S
ES
Baluom
Muhammad
M
Grossbard
Elliott B
EB
D000014:Abnormalities, Drug-Induced / Q000473:pathology*; D000631:Aminopyridines; D000818:Animals; D002478:Cells, Cultured; D047108:Embryonic Development / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000633:toxicity; D005260:Female; D007246:Infertility / Q000139:chemically induced / Q000453:epidemiology; D008297:Male; D009025:Morpholines; D010078:Oxazines / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000473:pathology; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000633:toxicity*; D011743:Pyrimidines; D011817:Rabbits; D051381:Rats; D012098:Reproduction / Q000187:drug effects; D018675:Toxicity Tests / Q000379:methods
D000631:Aminopyridines; D004791:Enzyme Inhibitors; D009025:Morpholines; C510788:N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine; D010078:Oxazines; D011725:Pyridines; D011743:Pyrimidines; D051096:Proto-Oncogene Proteins c-ret; C523665:fostamatinib