Discovery and SAR exploration of a novel series of imidazo[4,5-b]pyrazin-2-ones as potent and selective mTOR kinase inhibitors
2011
Mortensen, Deborah S. | Perrin-Ninkovic, Sophie M. | Harris, Roy | Lee, Branden G.S. | Shevlin, Graziella | Hickman, Matt | Khambatta, Gody | Bisonette, Rene R. | Fultz, Kimberly E. | Sankar, Sabita
We report here the discovery of a novel series of selective mTOR kinase inhibitors. A series of imidazo[4,5-b]pyrazin-2-ones, represented by screening hit 1, was developed into lead compounds with excellent mTOR potency and exquisite kinase selectivity. Potent compounds from this series show >1000-fold selectivity over the related PI3Kα lipid kinase. Further, compounds such as 2 achieve mTOR pathway inhibition, blocking both mTORC1 and mTORC2 signaling, in PC3 cancer cells as measured by inhibition of pS6 and pAkt (S473).
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