posted on 2021-10-26, 20:19authored byJaclyn R. Patterson, Alan P. Graves, Patrick Stoy, Mui Cheung, Tina A. Desai, Harvey Fries, Gregory J. Gatto, Dennis A. Holt, Lisa Shewchuk, Rachel Totoritis, Liping Wang, Lara S. Kallander
A series of diarylurea inhibitors
of the cardiac-specific kinase
TNNI3K were developed to elucidate the biological function of TNNI3K
and evaluate TNNI3K as a therapeutic target for the treatment of cardiovascular
diseases. Utilizing a structure-based design, enhancements in kinase
selectivity were engineered into the series, capitalizing on the established
X-ray crystal structures of TNNI3K, VEGFR2, p38α, and B-Raf.
Our efforts culminated in the discovery of an in vivo tool compound 47 (GSK329), which exhibited desirable
TNNI3K potency and rat pharmacokinetic properties as well as promising
kinase selectivity against VEGFR2 (40-fold), p38α (80-fold),
and B-Raf (>200-fold). Compound 47 demonstrated positive
cardioprotective outcomes in a mouse model of ischemia/reperfusion
cardiac injury, indicating that optimized exemplars from this series,
such as 47, are favorable leads for discovering novel
medicines for cardiac diseases.