Discovery of a novel class of highly potent, selective, ATP-competitive, and orally bioavailable inhibitors of the mammalian target of rapamycin (mTOR)

…, J Cannoy, S Epshteyn, A Joshi, K Lara…

Index: Takeuchi, Craig S.; Kim, Byung Gyu; Blazey, Charles M.; Ma, Sunghoon; Johnson, Henry W. B.; Anand, Neel K.; Arcalas, Arlyn; Baik, Tae Gon; Buhr, Chris A.; Cannoy, Jonah; Epshteyn, Sergey; Joshi, Anagha; Lara, Katherine; Lee, Matthew S.; Wang, Longcheng; Leahy, James W.; Nuss, John M.; Aay, Naing; Aoyama, Ron; Foster, Paul; Lee, Jae; Lehoux, Isabelle; Munagala, Narsimha; Plonowski, Arthur; Rajan, Sharmila; Woolfrey, John; Yamaguchi, Kyoko; Lamb, Peter; Miller, Nicole Journal of Medicinal Chemistry, 2013 , vol. 56, # 6 p. 2218 - 2234

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Citation Number: 15

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) ...