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 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.