Discovery of a Novel Class of Highly Potent, Selective, ATP-Competitive, and Orally Bioavailable Inhibitors of the Mammalian Target of Rapamycin (mTOR)
| Autor: | John Woolfrey, Craig Stacy Takeuchi, Arthur Plonowski, Kyoko Yamaguchi, Ron Aoyama, Byung Gyu Kim, Anagha Abhijit Joshi, Paul Foster, Sunghoon Ma, Sharmila Rajan, Tae Gon Baik, Naing Aay, Arlyn Arcalas, Charles M. Blazey, Jonah Cannoy, Peter Lamb, Isabelle Lehoux, Chris A. Buhr, Narsimha Munagala, Matthew Sangyup Lee, John M. Nuss, James W. Leahy, Jae Lee, Sergey Epshteyn, Neel Kumar Anand, Nicole Miller, Longcheng Wang, Katherine Lara, Henry Johnson |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Models Molecular Protein Conformation Administration Oral Biological Availability Pharmacology Binding Competitive Substrate Specificity Mice Adenosine Triphosphate Dogs Pharmacokinetics Oral administration Cell Line Tumor Drug Discovery Animals Humans Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Drug discovery Chemistry Kinase TOR Serine-Threonine Kinases Benzoxazines Rats Bioavailability Cell culture Molecular Medicine Phosphorylation Female |
| Zdroj: | Journal of Medicinal Chemistry. 56:2218-2234 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm3007933 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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