1. Discovery of triazine-benzimidazoles as selective inhibitors of mTOR.
- Author
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Peterson EA, Andrews PS, Be X, Boezio AA, Bush TL, Cheng AC, Coats JR, Colletti AE, Copeland KW, DuPont M, Graceffa R, Grubinska B, Harmange JC, Kim JL, Mullady EL, Olivieri P, Schenkel LB, Stanton MK, Teffera Y, Whittington DA, Cai T, and La DS
- Subjects
- Benzimidazoles chemistry, Cell Line, Tumor, Crystallography, X-Ray, Humans, Hydrogen Bonding, Inhibitory Concentration 50, Models, Molecular, Structure-Activity Relationship, Triazines chemistry, Benzimidazoles pharmacology, Drug Discovery, TOR Serine-Threonine Kinases antagonists & inhibitors, Triazines pharmacology
- Abstract
mTOR is part of the PI3K/AKT pathway and is a central regulator of cell growth and survival. Since many cancers display mutations linked to the mTOR signaling pathway, mTOR has emerged as an important target for oncology therapy. Herein, we report the discovery of triazine benzimidazole inhibitors that inhibit mTOR kinase activity with up to 200-fold selectivity over the structurally homologous kinase PI3Kα. When tested in a panel of cancer cell lines displaying various mutations, a selective inhibitor from this series inhibited cellular proliferation with a mean IC(50) of 0.41 μM. Lead compound 42 demonstrated up to 83% inhibition of mTOR substrate phosphorylation in a murine pharmacodynamic model., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
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