| Literature DB >> 23394126 |
Craig S Takeuchi1, Byung Gyu Kim, Charles M Blazey, Sunghoon Ma, Henry W B Johnson, Neel K Anand, Arlyn Arcalas, Tae Gon Baik, Chris A Buhr, Jonah Cannoy, Sergey Epshteyn, Anagha Joshi, Katherine Lara, Matthew S Lee, Longcheng Wang, James W Leahy, John M Nuss, Naing Aay, Ron Aoyama, Paul Foster, Jae Lee, Isabelle Lehoux, Narsimha Munagala, Arthur Plonowski, Sharmila Rajan, John Woolfrey, Kyoko Yamaguchi, Peter Lamb, Nicole Miller.
Abstract
A series of novel, highly potent, selective, and ATP-competitive mammalian target of rapamycin (mTOR) inhibitors based on a benzoxazepine scaffold have been identified. Lead optimization resulted in the discovery of inhibitors with low nanomolar activity and greater than 1000-fold selectivity over the closely related PI3K kinases. Compound 28 (XL388) inhibited cellular phosphorylation of mTOR complex 1 (p-p70S6K, pS6, and p-4E-BP1) and mTOR complex 2 (pAKT (S473)) substrates. Furthermore, this compound displayed good pharmacokinetics and oral exposure in multiple species with moderate bioavailability. Oral administration of compound 28 to athymic nude mice implanted with human tumor xenografts afforded significant and dose-dependent antitumor activity.Entities:
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Year: 2013 PMID： 23394126 DOI： 10.1021/jm3007933
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446