| Identification |
| Chemical Name |
AZD-8055 |
| Accession Number |
HAMDB165 |
| Alternative Names |
AZD8055;AZD 8055 |
| IUPAC Name |
[5-[2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2-methoxyphenyl]methanol |
| Formula |
C25H31N5O4 |
| Canonical SMILES |
CC1COCCN1C2=NC(=NC3=C2C=CC(=N3)C4=CC(=C(C=C4)OC)CO)N5CCOCC5C |
| Structure |
C4=CC(=C(C=C4)OC)CO)N5CCOCC5C/PNG)
|
| Physicochemical Properties |
| Molecular Weight |
465.545Molecular weight |
| Hbond Donor |
1Number of hydrogen bond acceptor atoms
(not counting acidic atoms but counting atoms that are both hydrogen bond donors and acceptors such as -OH).
|
| Hbond Acceptor |
7
Number of hydrogen bond donor atoms (not counting basic atoms but counting atoms that are both hydrogen bond donors and acceptors such as -OH).
|
| logP (o/w) |
1.990
Log of the octanol/water partition coefficient (including implicit hydrogens). [LOGP 1998]
|
| logS |
-6.335
Log of the aqueous solubility (mol/L).
|
| MR |
12.848
Molecular refractivity (including implicit hydrogens).
|
| SlogP |
2.909
Log of the octanol/water partition coefficient. [Crippen 1999]
|
| TPSA |
93.070
Polar surface area (Å2) calculated using group contributions to approximate the polar surface area from connection table information only. The parameterization is that of Ertl et al. [Ertl 2000].
|
| logD (PH=7) |
1.712
The octanol/water distribution coefficient at pH 7.
|
| pKa (PH=7) |
14.000
The pKa of the reaction that removes a proton from the ensemble of states with a hydrogen count equal to the input structure.
|
| pKb (PH=7) |
7.228
The pKb of the reaction that adds a proton from the ensemble of states with a hydrogen count equal to the input structure.
|
| Lipinski druglike |
1
One if and only if lip_violation < 2 otherwise zero.
|
| Solubility |
10 mM in DMSO |
| Role in Autophagy |
| Not Available |
| Biological Behaviors |
| Gene Name |
MTOR |
| Target |
Autophagy; mTOR; |
| Pathway |
- Autophagy
- PI3K/Akt/mTOR
|
| Biological Description |
AZD8055 is a novel ATP-competitive mTOR inhibitor with IC50 of 0.8 nM with excellent selectivity (～1,000-fold) against PI3K isoforms and ATM/DNA-PK. |
| Research Area |
Cancer |
| Category |
Activator |
| In Vitro |
The inhibitory activity of AZD-8055 (AZD8055) against mTOR is evaluated using two different assays. Using the truncated recombinant mTOR enzyme, the IC50 for AZD8055 is 0.13±0.05 nM. Using native mTOR enzyme complexes extracted from HeLa cells, the IC50 is 0.8±0.2 nM. AZD-8055 (AZD8055) shows excellent selectivity (∼1,000-fold) against all class I PI3K isoforms and other members of the PI3K-like kinase family. AZD-8055 inhibits the phosphorylation of mTORC1 substrates p70S6K and 4E-BP1 as well as phosphorylation of the mTORC2 substrate AKT and downstream proteins. The cellular IC50s for AZD8055 are calculated as 24±9 nM (n=13) for pAKT Ser473 and 27±3 nM (n=12) for pS6 Ser235/236 in MDA-MB-468 cells. |
| In Vivo |
In mice bearing U87-MG (PTEN null) glioblastoma xenografts, oral treatment with AZD-8055 (AZD8055) results in a dose-dependent tumor growth inhibition of 33%, 48%, and 77% with 2.5, 5, and 10 mg/kg/d twice daily, respectively. A similar dose dependency is observed in nude mice bearing A549 xenografts: tumor growth inhibition is 44%, 55%, and 93% after 2.5, 5, and 10 mg/kg/d twice daily, respectively. AZD8055 also results in significant inhibition of tumor growth and/or regression in breast, lung, colon, prostate, and uterine xenograft models when administered either twice daily at 10 mg/kg or daily at a dose of 20 mg/kg. AZD8055 markedly decreases the phosphorylation levels of mTOR and its substrates and the activation of microglia in vivo, and promotes the microglial polarization from M1 phenotype to M2 phenotype. In addition, administration of AZD8055 following subarachnoid hemorrhage (SAH) significantly ameliorates EBI, including neuronal apoptosis, neuronal necrosis, brain edema and blood-brain barrier permeability. |
| Clinical Trial |
Phase 1 |
| External Links |
| CAS Numbers |
1009298-09-2 |
| Pubchem |
25262965 |
| HMDB |
Not Available |
| DrugBank |
Not Available |
| References |
- Chresta Cm, Davies Br, Hickson I, Harding T, Cosulich S, Critchlow Se, Vincent Jp, Ellston R, Jones D, Sini P, James D, Howard Z, Dudley P, Hughes G, Smith L, Maguire S, Hummersone M, Malagu K, Menear K, Jenkins R, Jacobsen M, Smith Gc, Guichard S, Pass M, Azd8055 Is A Potent, Selective, And Orally Bioavailable Atp-competitive Mammalian Target Of Rapamycin Kinase Inhibitor With In Vitro And In Vivo Antitumor Activity., Cancer Res.2010 Jan 1;70(1):288-98. Doi: 10.1158/0008-5472.can-09-1751. [PMID:20028854 ]
- You W, Wang Z, Li H, Shen H, Xu X, Jia G, Chen G, Inhibition Of Mammalian Target Of Rapamycin Attenuates Early Brain Injury Through Modulating Microglial Polarization After Experimental Subarachnoid Hemorrhage In Rats., J Neurol Sci.2016 Aug 15;367:224-31. Doi: 10.1016/j.jns.2016.06.021. [PMID:27423593 ]
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