AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity.
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 (approximately 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 micromol/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.
Chresta
Christine M
CM
AstraZeneca, Cheshire, United Kingdom. Christine.Chresta@astrazeneca.com
Davies
Barry R
BR
Hickson
Ian
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Harding
Tom
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Cosulich
Sabina
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Critchlow
Susan E
SE
Vincent
John P
JP
Ellston
Rebecca
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Jones
Darren
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Sini
Patrizia
P
James
Dominic
D
Howard
Zoe
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Dudley
Phillippa
P
Hughes
Gareth
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Smith
Lisa
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Maguire
Sharon
S
Hummersone
Marc
M
Malagu
Karine
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Menear
Keith
K
Jenkins
Richard
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Jacobsen
Matt
M
Smith
Graeme C M
GC
Guichard
Sylvie
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Pass
Martin
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D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology*; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D009025:Morpholines; D047428:Protein Kinase Inhibitors; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases