Description
AZD8055 (1009298-09-2) is a potent and highly selective inhibitor of mammalian target of rapamycin kinase (mTOR) kinase (IC50 = 0.8 nM).1,2 mTOR acts as a nutrient/energy/redox sensor and a controller of protein synthesis – as such it is a very important target for cancer research. It has been investigated as a potential chemotherapeutic for various cancers.3-7
Uses
A potent, selective, and orally bioavailable ATP-competitive mTOR kinase inhibitor with an IC50 of 0.8 nM. It inhibits the phosphorylation of mTORC1 substrates p70S6K and 4E-BP1 as well as phosphoryla
tion 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-dep
endent 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 S
6 and phosphorylated AKT at plasma concentrations leading to tumor growth inhibition.
Definition
ChEBI: AZD-8055 is a pyridopyrimidine that is pyrido[2,3-d]pyrimidine which is substituted at positions 2 and 4 by (3S)-3-methylmorpholin-4-yl groups and at position 5 by a 3-(hydroxymethyl)-4-methoxyphenyl group. It is an mTOR complex 1/2 (mTORC1/2) dual inhibitor [mTOR = mammalian target of rapamycin]. It has a role as a mTOR inhibitor, an apoptosis inducer and an antineoplastic agent. It is a member of benzyl alcohols, a tertiary amino compound, a pyridopyrimidine and a member of morpholines.
References
[1] CHRISTINE M CHRESTA. AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity.[J]. Cancer research, 2010, 70 1: 288-298. DOI:
10.1158/0008-5472.can-09-1751[2] KURT G. PIKE . Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: The discovery of AZD8055 and AZD2014[J]. Bioorganic & Medicinal Chemistry Letters, 2013, 23 5: Pages 1212-1216. DOI:
10.1016/j.bmcl.2013.01.019[3] SARAH V HOLT. Enhanced apoptosis and tumor growth suppression elicited by combination of MEK (selumetinib) and mTOR kinase inhibitors (AZD8055).[J]. Cancer research, 2012: 1804-1813. DOI:
10.1158/0008-5472.can-11-1780[4] L WILLEMS. The dual mTORC1 and mTORC2 inhibitor AZD8055 has anti-tumor activity in acute myeloid leukemia[J]. Leukemia, 2011, 26 6: 1195-1202. DOI:
10.1038/leu.2011.339[5] SHAORU LI. The mTOR inhibitor AZD8055 inhibits proliferation and glycolysis in cervical cancer cells.[J]. Oncology Letters, 2013: 717-721. DOI:
10.3892/ol.2012.1058[6] QIANG LI . The dual mTORC1 and mTORC2 inhibitor AZD8055 inhibits head and neck squamous cell carcinoma cell growth in vivo and in vitro[J]. Biochemical and biophysical research communications, 2013, 440 4: Pages 701-706. DOI:
10.1016/j.bbrc.2013.09.130[7] MIN HU. AZD8055 induces cell death associated with autophagy and activation of AMPK in hepatocellular carcinoma.[J]. Oncology reports, 2014: 649-656. DOI:
10.3892/or.2013.2890
