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MedKoo CAT#: 200312
Description: AZD-8055 is an inhibitor of the mammalian target of rapamycin (mTOR) with potential antineoplastic activity. mTOR kinase inhibitor AZD8055 inhibits the serine/threonine kinase activity of mTOR, resulting in decreased expression of mRNAs necessary for cell cycle progression, which may induce cell cycle arrest and tumor cell apoptosis. mTOR phosphorylates transcription factors, such as S6K1 and 4E-BP1, which stimulate protein synthesis and regulate cell growth, proliferation, motility, and survival.
MedKoo Cat#: 200312
Chemical Formula: C25H31N5O4
Exact Mass: 465.2376
Molecular Weight: 465.54
Elemental Analysis: C, 64.50; H, 6.71; N, 15.04; O, 13.75
Synonym: AZD8055; AZD-8055; AZD 8055.
IUPAC/Chemical Name: (5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol.
InChi Key: KVLFRAWTRWDEDF-IRXDYDNUSA-N
InChi Code: InChI=1S/C25H31N5O4/c1-16-14-33-10-8-29(16)24-20-5-6-21(18-4-7-22(32-3)19(12-18)13-31)26-23(20)27-25(28-24)30-9-11-34-15-17(30)2/h4-7,12,16-17,31H,8-11,13-15H2,1-3H3/t16-,17-/m0/s1
SMILES Code: OCC1=CC(C2=NC3=NC(N4[C@@H](C)COCC4)=NC(N5[C@@H](C)COCC5)=C3C=C2)=CC=C1OC
AZD8055 is 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. ( Source: Cancer Res; 70(1); 288-98 ).
1: Holt SV, Logie A, Davies BR, Alferez D, Runswick S, Fenton S, Chresta CM, Gu Y, Zhang J, Wu YL, Wilkinson RW, Guichard S, Smith PD. Enhanced apoptosis and tumor growth suppression elicited by combination of MEK and mTOR kinase inhibitors. Cancer Res. 2012 Jan 23. [Epub ahead of print] PubMed PMID: 22271687.
2: Zhang W, Khatibi NH, Yamaguchi-Okada M, Yan J, Chen C, Hu Q, Meng H, Han H, Liu S, Zhou C. Mammalian target of rapamycin (mTOR) inhibition reduces cerebral vasospasm following a subarachnoid hemorrhage injury in canines. Exp Neurol. 2011 Dec 8. [Epub ahead of print] PubMed PMID: 22177999.
3: Willems L, Chapuis N, Puissant A, Maciel TT, Green AS, Jacque N, Vignon C, Park S, Guichard S, Herault O, Fricot A, Hermine O, Moura IC, Auberger P, Ifrah N, Dreyfus F, Bonnet D, Lacombe C, Mayeux P, Bouscary D, Tamburini J. The dual mTORC1 and mTORC2 inhibitor AZD8055 has anti-tumor activity in acute myeloid leukemia. Leukemia. 2011 Dec 6. doi: 10.1038/leu.2011.339. [Epub ahead of print] PubMed PMID: 22143671.
4: Huang S, Yang ZJ, Yu C, Sinicrope FA. Inhibition of mTOR kinase by AZD8055 can antagonize chemotherapy-induced cell death through autophagy induction and down-regulation of p62/sequestosome 1. J Biol Chem. 2011 Nov 18;286(46):40002-12. Epub 2011 Sep 23. PubMed PMID: 21949121; PubMed Central PMCID: PMC3220585.
5: Shao H, Gao C, Tang H, Zhang H, Roberts LR, Hylander BL, Repasky EA, Ma WW, Qiu J, Adjei AA, Dy GK, Yu C. Dual targeting of mTORC1/C2 complexes enhances histone deacetylase inhibitor-mediated anti-tumor efficacy in primary HCC cancer in vitro and in vivo. J Hepatol. 2012 Jan;56(1):176-83. Epub 2011 Aug 9. PubMed PMID: 21835141.
6: Shi H, Kong X, Ribas A, Lo RS. Combinatorial treatments that overcome PDGFRβ-driven resistance of melanoma cells to V600EB-RAF inhibition. Cancer Res. 2011 Aug 1;71(15):5067-74. PubMed PMID: 21803746; PubMed Central PMCID: PMC3149831.
7: Jiang Q, Weiss JM, Back T, Chan T, Ortaldo JR, Guichard S, Wiltrout RH. mTOR kinase inhibitor AZD8055 enhances the immunotherapeutic activity of an agonist CD40 antibody in cancer treatment. Cancer Res. 2011 Jun 15;71(12):4074-84. Epub 2011 May 3. PubMed PMID: 21540234; PubMed Central PMCID: PMC3116937.
8: Marshall G, Howard Z, Dry J, Fenton S, Heathcote D, Gray N, Keen H, Logie A, Holt S, Smith P, Guichard SM. Benefits of mTOR kinase targeting in oncology: pre-clinical evidence with AZD8055. Biochem Soc Trans. 2011 Apr;39(2):456-9. Review. PubMed PMID: 21428919.
9: GarcÃa-MartÃnez JM, Wullschleger S, Preston G, Guichard S, Fleming S, Alessi DR, Duce SL. Effect of PI3K- and mTOR-specific inhibitors on spontaneous B-cell follicular lymphomas in PTEN/LKB1-deficient mice. Br J Cancer. 2011 Mar 29;104(7):1116-25. Epub 2011 Mar 15. PubMed PMID: 21407213; PubMed Central PMCID: PMC3068512.
10: Houghton PJ, Gorlick R, Kolb EA, Lock R, Carol H, Morton CL, Keir ST, Reynolds CP, Kang MH, Phelps D, Maris JM, Billups C, Smith MA. Initial testing (stage 1) of the mTOR kinase inhibitor AZD8055 by the pediatric preclinical testing program. Pediatr Blood Cancer. 2012 Feb;58(2):191-9. doi: 10.1002/pbc.22935. Epub 2011 Feb 18. PubMed PMID: 21337679.