Discovery of a Novel Class of Highly Potent, Selective, ATP-Competitive, and Orally Bioavailable Inhibitors of the Mammalian Target of Rapamycin (mTOR)

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• 作者：Craig S. Takeuchi ; 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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March 28, 2013
• 年：2013
• 卷：56
• 期：6
• 页码：2218-2234
• 全文大小：695K
• 年卷期：v.56,no.6(March 28, 2013)
• ISSN：1520-4804

文摘

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 <b>28b> (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 <b>28b> to athymic nude mice implanted with human tumor xenografts afforded significant and dose-dependent antitumor activity.