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

作者：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

来源：Cancer Research, 2010, 70(1): 288-298.

DOI：10.1158/0008-5472.CAN-09-1751

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 IC(50) of 0.8 nmol/L. AZD8055 showed excellent selectivity (similar to 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 mu mol/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.

• 出版日期2010-1-1