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Imidazo[1,5-a]pyrazines: orally efficacious inhibitors of mTORC1 and mTORC2 |
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| Authors: | Crew Andrew P Bhagwat Shripad V Dong Hanqing Bittner Mark A Chan Anna Chen Xin Coate Heather Cooke Andrew Gokhale Prafulla C Honda Ayako Jin Meizhong Kahler Jennifer Mantis Christine Mulvihill Mark J Tavares-Greco Paula A Volk Brian Wang Jing Werner Douglas S Arnold Lee D Pachter Jonathan A Wild Robert Gibson Neil W |
| Affiliation: | a (OSI) Oncology, OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive, Farmingdale, NY 11735, USA b (OSI) Oncology, OSI Pharmaceuticals, Inc., 2860 Wilderness Place, Boulder, CO 80301, USA |
| Abstract: | The discovery and optimization of a series of imidazo[1,5-a]pyrazine inhibitors of mTOR is described. HTS hits were optimized for potency, selectivity and metabolic stability to provide the orally bioavailable proof of concept compound 4c that demonstrated target inhibition in vivo and concomitant inhibition of tumor growth in an MDA-MB-231 xenograft model. |
| Keywords: | mTOR mTORC1 mTORC2 Imidazo[1,5-a]pyrazine Oral inhibitor |
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