AZD8055 Is a Potent, Selective, and Orally Bioavailable ATP-Competitive Mammalian Target of Rapamycin Kinase Inhibitor with In vitro and In vivo Antitumor Activity
Top Cited Papers
- 1 January 2010
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 70 (1), 288-298
- https://doi.org/10.1158/0008-5472.can-09-1751
Abstract
The mammalian target of rapamycin (mTOR) kinase forms two multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, cell survival, and autophagy. Allosteric inhibitors of mTORC1, such as rapamycin, have been extensively used to study tumor cell growth, proliferation, and autophagy but have shown only limited clinical utility. Here, we describe AZD8055, a novel ATP-competitive inhibitor of mTOR kinase activity, with an IC50 of 0.8 nmol/L. AZD8055 showed excellent selectivity (∼1,000-fold) against all class I phosphatidylinositol 3-kinase (PI3K) isoforms and other members of the PI3K-like kinase family. Furthermore, there was no significant activity against a panel of 260 kinases at concentrations up to 10 μmol/L. AZD8055 inhibits the phosphorylation of mTORC1 substrates p70S6K and 4E-BP1 as well as phosphorylation of the mTORC2 substrate AKT and downstream proteins. The rapamycin-resistant T37/46 phosphorylation sites on 4E-BP1 were fully inhibited by AZD8055, resulting in significant inhibition of cap-dependent translation. In vitro, AZD8055 potently inhibits proliferation and induces autophagy in H838 and A549 cells. In vivo, AZD8055 induces a dose-dependent pharmacodynamic effect on phosphorylated S6 and phosphorylated AKT at plasma concentrations leading to tumor growth inhibition. Notably, AZD8055 results in significant growth inhibition and/or regression in xenografts, representing a broad range of human tumor types. AZD8055 is currently in phase I clinical trials. Cancer Res; 70(1); 288–98Keywords
Other Versions
This publication has 35 references indexed in Scilit:
- mTORC1 signalling and mRNA translationBiochemical Society Transactions, 2009
- Defining the Role of mTOR in CancerCancer Cell, 2007
- The Rheb Switch 2 Segment Is Critical for Signaling to Target of Rapamycin Complex 1Published by Elsevier BV ,2007
- Prolonged Rapamycin Treatment Inhibits mTORC2 Assembly and Akt/PKBMolecular Cell, 2006
- Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2Genes & Development, 2005
- Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR ComplexScience, 2005
- Nutrient sensing and metabolic decisionsComparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology, 2004
- Inappropriate Activation of the TSC/Rheb/mTOR/S6K Cassette Induces IRS1/2 Depletion, Insulin Resistance, and Cell Survival DeficienciesCurrent Biology, 2004
- The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stressProceedings of the National Academy of Sciences of the United States of America, 2004
- Insulin-induced insulin receptor substrate-1 degradation is mediated by the proteasome degradation pathway.Diabetes, 1999