Discovery of Potent and Selective Inhibitors of the Mammalian Target of Rapamycin (mTOR) Kinase
| Autor: | David Malwitz, Irwin Hollander, Kevin J. Curran, Arie Zask, John W. Ellingboe, Lourdes Toral-Barza, Yongbo Hu, Weiguo Zhang, Pawel Nowak, Joshua Kaplan, Natasja Brooijmans, Matthew Gregory Bursavich, Derek C. Cole, Jeroen C. Verheijen, James Joseph Gibbons, Ker Yu |
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| Rok vydání: | 2009 |
| Předmět: |
Models
Molecular Cell growth Kinase Angiogenesis Chemistry TOR Serine-Threonine Kinases High-throughput screening RPTOR Molecular Conformation mTORC1 Binding Competitive mTORC2 Substrate Specificity Molecular Weight Inhibitory Concentration 50 Pyrimidines Biochemistry Cell Line Tumor Drug Discovery Humans Molecular Medicine Protein Kinase Inhibitors Protein Kinases PI3K/AKT/mTOR pathway Signal Transduction |
| Zdroj: | Journal of Medicinal Chemistry. 52:7081-7089 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm9012642 |
| Popis: | The mammalian target of rapamycin (mTOR) is a central regulator of cell growth, metabolism, and angiogenesis and an emerging target in cancer research. High throughput screening (HTS) of our compound collection led to the identification of 3-(4-morpholin-4-yl-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol (5a), a modestly potent and nonselective inhibitor of mTOR and phosphoinositide 3-kinase (PI3K). Optimization of compound 5a, employing an mTOR homology model based on an X-ray crystal structure of closely related PI3Kgamma led to the discovery of 6-(1H-indol-5-yl)-4-morpholin-4-yl-1-[1-(pyridin-3-ylmethyl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine (5u), a potent and selective mTOR inhibitor (mTOR IC(50) = 9 nM; PI3Kalpha IC(50) = 1962 nM). Compound 5u selectively inhibited cellular biomarker of mTORC1 (P-S6K, P-4EBP1) and mTORC2 (P-AKT S473) over the biomarker of PI3K/PDK1 (P-AKT T308) and did not inhibit PI3K-related kinases (PIKKs) in cellular assays. These pyrazolopyrimidines represent an exciting new series of mTOR-selective inhibitors with potential for development for cancer therapy. |
| Databáze: | OpenAIRE |
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