AZD2014

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Background

AZD2014 is a novel, potent and highly selective dual inhibitor of the mammalian rapamycin (mTORC1 and mTORC2) with an IC50 value of 2.8 nM. It is an oral inhibitor and possesses potential antineoplastic activity. AZD2014 enhanced susceptibility of glioblastoma stem-like cells (GSCs) to irradiation both in vitro and under orthotopic in vivo conditions. Kahn J et al pretreated CD133+ and CD15+ GSC cells with AZD2014 (2 µM) for 1 hour, followed by irradiation. The effect was then measured by clonogenic survival analysis [2]. Using in vitro screening, they demonstrated that the combination of ibrutinib, an inhibitor of the tyrosine kinase BTK, and AZD2014 could dramatically induce apoptosis in ABC-subtype DLBCL cell lines. Thereby, the combination of AZD2014 with a BTK inhibitor is a promising therapeutic method to cure patients with ABC-type DLBCL [3]. In hepatocellular carcinoma cells, AZD2014 gave rise to a more complete inhibition of mTORC1 than rapamycin, while the inhibition of mTORC2 prevented the feedback activation of AKT signaling. Therefore, AZD2014 was identified to be more efficacious in the induction of apoptosis, autophagy, and cell cycle arrest, resulting in a significant proliferation suppression of the cells, in contrast with rapamycin [4].In a recent human pharmacokinetic and pharmacodynamic study, a dose of 50mg BD(twice a day)AZD2014 was recommended to achieve pharmacologically relevant plasma concentrations [5].

Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: the discovery of AZD8055 and AZD2014. Bioorg Med Chem Lett. 2013 Mar 1;23(5):1212-6.
The mTORC1/mTORC2 inhibitor AZD2014 enhances the radiosensitivity of glioblastoma stem-like cells. Neuro Oncol. 2014 Jan;16(1):29-37.
Synergistic induction of apoptosis by combination of BTK and dual mTORC1/2 inhibitors in diffuse large B cell lymphoma. Oncotarget. 2014 Jul 15;5(13):4990-5001.
Dramatic antitumor effects of the dual mTORC1 and mTORC2 inhibitor AZD2014 in hepatocellular carcinoma. Am J Cancer Res. 2014 Dec 15;5(1):125-39. eCollection 2015.
First-in-human pharmacokinetic and pharmacodynamic study of the dual m-TORC 1/2 inhibitor, AZD2014. Clin Cancer Res. 2015 Mar 24. pii: clincanres.2422.2014.