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

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

  • J Med Chem. 2013 Mar 28;56(6):2218-34. doi: 10.1021/jm3007933.
Craig S Takeuchi 1,  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
Affiliations

Affiliation

  • 1 Department of Drug Discovery, Exelixis , 169 Harbor Way, South San Francisco, California 94083, USA.
PMID: 23394126 DOI: 10.1021/jm3007933
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.

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