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Cited by 812PI3K/AKT/mTOR signaling in cancerAutophagy in Disease and TherapyMetabolism, Diabetes, and Cancer

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AZD8055 Is a Potent, Selective, and Orally Bioavailable ATP-Competitive Mammalian Target of Rapamycin Kinase Inhibitor with In vitro and In vivo Antitumor Activity

Chresta, Christine M., Davies, Barry R., Hickson, Ian, Harding, Tom, Cosulich, Sabina, Critchlow, Susan E., Vincent, John P., Ellston, Rebecca, Jones, Darren, Sini, Patrizia, James, Dominic, Howard, Zoe, Dudley, Phillippa, Hughes, Gareth, Smith, Lisa, Maguire, Sharon, Hummersone, Marc, Malagu, Karine, Menear, Keith, Jenkins, Richard, Jacobsen, Matt, Smith, Graeme C.M., Guichard, Sylvie, Pass, Martin·2010·Cancer Research
DOI 10.1158/0008-5472.can-09-1751

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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); 288–98

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Research works printed but not linked: 30

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Metadata

Authors
Chresta, C. M., Davies, B. R., Hickson, I., Harding, T., Cosulich, S., Critchlow, S. E., Vincent, J. P., Ellston, R., Jones, D., Sini, P., James, D., Howard, Z., Dudley, P., Hughes, G., Smith, L., Maguire, S., Hummersone, M., Malagu, K., Menear, K., Jenkins, R., Jacobsen, M., Smith, G. C. M., Guichard, S., & Pass, M.
Affiliations
  • AstraZeneca (United Kingdom) (GB)
  • Authors' Affiliations: 1AstraZeneca, Cheshire, United Kingdom and 2KuDOS Pharmaceuticals Ltd., Cambridge, United Kingdom
Corresponding author
Chresta, Christine M.
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2010-01-01
Volume
70
Issue
1
Pages
288-298
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-09-1751
OpenAlex
W2154836325
Cited by
812
References
6
Citations by year
2026: 22 · 2025: 37 · 2024: 41 · 2023: 30 · 2022: 37 · 2021: 47 · 2020: 47 · 2019: 54 · 2018: 37 · 2017: 51 · 2016: 55 · 2015: 67 · 2014: 63 · 2013: 84 · 2012: 52
FWCI
16.15
Type
journal article
Language
en
Open access
closed
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
Home Office
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
AZD8055, mTOR inhibitors, ATP-competitive inhibition, mTORC1, mTORC2, rapamycin resistance, 4E-BP1 phosphorylation, p70S6K, Akt phosphorylation, cap-dependent translation, autophagy, anticancer activity, xenografts, oral bioavailability, kinase selectivity
MeSH terms
Animals, Antineoplastic Agents, Female, Humans, Mice, Nude, Morpholines, Neoplasms, Experimental, Protein Kinases, Signal Transduction, Xenograft Model Antitumor Assays, Protein Kinase Inhibitors, Cell Proliferation, Mice, TOR Serine-Threonine Kinases

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