Discovery of triazine-benzimidazoles as selective inhibitors of mTOR
| Autor: | Philip R. Olivieri, Barbara Grubinska, Alan C. Cheng, Alessandro Boezio, Katrina W. Copeland, Yohannes Teffera, Daniel S. La, Xuhai Be, James R. Coats, Paul S. Andrews, Jean-Christophe Harmange, Joseph L. Kim, Ti Cai, Emily A. Peterson, Michelle DuPont, Douglas A. Whittington, Laurie B. Schenkel, Adria E. Colletti, Mary K. Stanton, Tammy L. Bush, Russell Graceffa, Erin L. Mullady |
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| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular Clinical Biochemistry Pharmaceutical Science Crystallography X-Ray Biochemistry mTORC2 Inhibitory Concentration 50 Structure-Activity Relationship Cell Line Tumor Drug Discovery Humans Kinase activity Molecular Biology PI3K/AKT/mTOR pathway Chemistry Cell growth Kinase Drug discovery Triazines TOR Serine-Threonine Kinases Organic Chemistry RPTOR Hydrogen Bonding Cancer research Molecular Medicine Benzimidazoles Signal transduction |
| Zdroj: | Bioorganicmedicinal chemistry letters. 21(7) |
| ISSN: | 1464-3405 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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