AZD8055MTOR inhibitor CAS# 1009298-09-2 |
2D Structure
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Quality Control & MSDS
3D structure
Package In Stock
Number of papers citing our products
Cas No. | 1009298-09-2 | SDF | Download SDF |
PubChem ID | 25262965 | Appearance | Powder |
Formula | C25H31N5O4 | M.Wt | 465.54 |
Type of Compound | N/A | Storage | Desiccate at -20°C |
Solubility | DMSO : 33.33 mg/mL (71.59 mM; Need ultrasonic) | ||
Chemical Name | [5-[2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2-methoxyphenyl]methanol | ||
SMILES | CC1COCCN1C2=NC(=NC3=C2C=CC(=N3)C4=CC(=C(C=C4)OC)CO)N5CCOCC5C | ||
Standard InChIKey | KVLFRAWTRWDEDF-IRXDYDNUSA-N | ||
Standard InChI | 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 | ||
General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. |
Description | AZD8055 is a novel ATP-competitive inhibitor of mTOR with IC50 of 0.8 nM with excellent selectivity (∼1,000-fold) against PI3K isoforms and ATM/DNA-PK. | |||||
Targets | mTOR (full length) | mTOR (truncated) | ||||
IC50 | 0.8 nM | 0.13 nM |
Cell experiment: [1] | |
Cell lines | TamR and MCF7-X cells |
Preparation method | The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months. |
Reacting condition | 100 nM, 3 days |
Applications | The impact of AZD8055 on TamR and MCF-7-X cell proliferation was monitored using MIB1 Ki67 staining. Three days treatment with 50 nM AZD8055 reduced Ki67 staining in both TamR and MCF7-X cells and after treatment with 100 nM 40% to 50% of all cells were deemed negative for MIB1 indicating a significant exit from the cell cycle. |
Animal experiment: [2] | |
Animal models | Female C57BL/6 mice |
Dosage form | Intraperitoneal injection, 10 mg/kg |
Application | Overnight fasted mice were intraperitoneal-injected with either vehicle or AZD8055. 3 h after AZD8055 injection additional blood was sampled for plasma insulin and fatty acids (FA) determinations. Glucose levels in AZD8055 injected mice were elevated 3 and 6 h after drug injection but were similar to control mice at 24 h after drug injection. Along with elevated glucose levels at 3 h, AZD8055 treated mice had 3-fold higher plasma insulin levels and lower plasma FAs. |
Other notes | Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
References: [1] Jordan NJ, Dutkowski CM, Barrow D, Mottram HJ, Hutcheson IR, Nicholson RI, Guichard SM, Gee JM. Impact of dual mTORC1/2 mTOR kinase inhibitor AZD8055 on acquired endocrine resistance in breast cancer in vitro. Breast Cancer Res. 2014 Jan 23;16(1):R12. [2] Kleinert M, Sylow L, Fazakerley DJ, Krycer JR, Thomas KC, Oxbøll AJ, Jordy AB, Jensen TE, Yang G, Schjerling P, Kiens B, James DE, Ruegg MA, Richter EA. Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo. Mol Metab. 2014 Jun 27;3(6):630-41. |
AZD8055 Dilution Calculator
AZD8055 Molarity Calculator
1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
1 mM | 2.148 mL | 10.7402 mL | 21.4804 mL | 42.9609 mL | 53.7011 mL |
5 mM | 0.4296 mL | 2.148 mL | 4.2961 mL | 8.5922 mL | 10.7402 mL |
10 mM | 0.2148 mL | 1.074 mL | 2.148 mL | 4.2961 mL | 5.3701 mL |
50 mM | 0.043 mL | 0.2148 mL | 0.4296 mL | 0.8592 mL | 1.074 mL |
100 mM | 0.0215 mL | 0.1074 mL | 0.2148 mL | 0.4296 mL | 0.537 mL |
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. |
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AZD8055 is a selective inhibitor of mTOR kinase with IC50 of 0.8 nM [1]. It competes with ATP at the ATP-binding cleft of mTOR. AZD8055 showed ~1000 fold selectivity against closely related kinases PI3K isoforms and ATM/DNA-PK [1]. Furthermore, it had no significant activity against a panel of 260 kinases at 10 μM [1].
AZD8055 has shown potential anti-tumor activity in preclinical studies.
mTOR phosphorylates and activates transcription factors which in turn regulate cell growth, proliferation, motility, and survival. AZD8055 inhibited downstream signaling of both mTORC1 and mTORC2 complexes [1]. It inhibited proliferation in cell lines of lung, cervical and laryngeal cancer, as well as acute myeloid leukemia [1-4]. Studies in xenograft models showed that AZD8055 reduced tumor growth of glioblastoma, breast, lung, colon, prostate, uterine, and head and neck cancer [1, 5]. In addition, AZD8055 enhanced the efficacy of HDAC inhibitors and MEK inhibitors [6-8]. AZD8055 has been tested in phase I clinical trials with minimal clinical benefit [9, 10].
References:
[1]Chresta CM, Davies BR, Hickson I et al. 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; 70: 288-298.
[2]Li S, Li Y, Hu R et al. The mTOR inhibitor AZD8055 inhibits proliferation and glycolysis in cervical cancer cells. Oncol Lett 2013; 5: 717-721.
[3]Willems L, Chapuis N, Puissant A et al. The dual mTORC1 and mTORC2 inhibitor AZD8055 has anti-tumor activity in acute myeloid leukemia. Leukemia 2012; 26: 1195-1202.
[4]Zhao L, Teng B, Wen L et al. mTOR inhibitor AZD8055 inhibits proliferation and induces apoptosis in laryngeal carcinoma. Int J Clin Exp Med 2014; 7: 337-347.
[5]Li Q, Song XM, Ji YY et al. The dual mTORC1 and mTORC2 inhibitor AZD8055 inhibits head and neck squamous cell carcinoma cell growth in vivo and in vitro. Biochem Biophys Res Commun 2013; 440: 701-706.
[6]Shao H, Gao C, Tang H et al. 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; 56: 176-183.
[7]Holt SV, Logie A, Davies BR et al. Enhanced apoptosis and tumor growth suppression elicited by combination of MEK (selumetinib) and mTOR kinase inhibitors (AZD8055). Cancer Res 2012; 72: 1804-1813.
[8]Renshaw J, Taylor KR, Bishop R et al. Dual blockade of the PI3K/AKT/mTOR (AZD8055) and RAS/MEK/ERK (AZD6244) pathways synergistically inhibits rhabdomyosarcoma cell growth in vitro and in vivo. Clin Cancer Res 2013; 19: 5940-5951.
[9]Asahina H, Nokihara H, Yamamoto N et al. Safety and tolerability of AZD8055 in Japanese patients with advanced solid tumors; a dose-finding phase I study. Invest New Drugs 2013; 31: 677-684.
[10]Naing A, Aghajanian C, Raymond E et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma. Br J Cancer 2012; 107: 1093-1099.
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mTOR inhibitor AZD8055 inhibits proliferation and induces apoptosis in laryngeal carcinoma.[Pubmed:24600487]
Int J Clin Exp Med. 2014 Feb 15;7(2):337-47. eCollection 2014.
The mammalian target of rapamycin (mTOR) kinase forms two multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, 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, against all class I phosphatidylinositol3-kinase (PI3K) and other members of the PI3K-like kinase family. The study was to determine the effect of AZD8055 on proliferation and apoptosis on Hep-2, a human laryngeal cancer cell line and to investigate the underlying mechanism(s) of action. Hep-2 cells were treated with AZD8055 for 24, 48 or 72 h. MTT was used to determine cell proliferation. Rhodamine 123 and TUNEL staining were used to determine mitochondrial membrane potential and cell apoptosis analyzed by fluorescence-activated cell sorting (FACS). Protein expressions were examined by western blotting. Treatment with AZD8055 inhibited proliferation and induced apoptosis in Hep-2 cells in a dose- and time-dependent manner. During the prolonged treatment with AZD8055, AZD8055 inhibits the mammalian target of rapamycin mTOR. Further experiments showed which signaling cascade p-4EBP1 and substrate EIF4E as well as downstream proteins were down regulated. Furthermore, our study showed that the expression profiles of various BH3-only proteins including Bid, Bad, and Bim, apoptosis regulatory protein cleaved caspase3 was up regulated in a time-dependent manner in Hep-2 cells treated with AZD8055. Thus, in vitro, AZD8055 potently inhibits proliferation and induces apoptosis in head and neck squamous cell carcinoma.
HSP90 inhibitor AUY922 abrogates up-regulation of RTKs by mTOR inhibitor AZD8055 and potentiates its antiproliferative activity in human breast cancer.[Pubmed:24706460]
Int J Cancer. 2014 Nov 15;135(10):2462-74.
mTOR inhibition led to activation of upstream receptor tyrosine kinases (RTKs) and AKT, which may attenuate the efficacy of mTOR kinase inhibitors. We sought to discover efficient drug combination with mTOR inhibitors by elucidating the survival feedback loops induced by mTOR inhibition in breast cancer. The feedback signaling upon treatment of mTOR inhibitor AZD8055 was determined and the combinatorial activity of AZD8055 and HSP90 inhibitor AUY922 in cell signaling and proliferation were detected. Treatment of breast cancer T47D cells with AZD8055 induced activation of AKT and phosphatidylinositol 3-kinase (PI3K), which was accompanied with increase in expression of multiple upstream proteins including EGFR, HER2, HER3 and IRS-1. Different RTKs were revealed to be responsible for the reactivation of AKT by AZD8055 in different breast cancer cell lines. Down-regulation of these proteins differentially enhanced the antiproliferative activity of AZD8055. AZD8055 and AUY922 displayed synergistic effect against a panel of human breast cancer cells irrespective their genotype, which was associated with enhanced cell cycle arrest and inhibition of DNA synthesis. AUY922 destabilized multiple tested tyrosine kinases and abrogated activation of AKT induced by AZD8055. AZD8055 also inhibited up-regulation of HSP70 and HSP27 upon AUY922 treatment. Cotreatment of these two drugs demonstrated synergistic activity against triple negative MDA-MB-468 xenograft without enhanced toxicity. The combination of AZD8055 and AUY922 demonstrated synergistic activity against various types of breast cancer and established a mechanistic rationale for a combination approach using catalytic mTOR kinase inhibitor and HSP90 inhibitor in the treatment of breast cancer.
The mTORC1/2 Inhibitor AZD8055 Strengthens the Efficiency of the MEK Inhibitor Trametinib to Reduce the Mcl-1/[Bim and Puma] ratio and to Sensitize Ovarian Carcinoma Cells to ABT-737.[Pubmed:27980105]
Mol Cancer Ther. 2017 Jan;16(1):102-115.
The identification of novel therapeutic strategies is an important urgent requirement for the clinical management of ovarian cancer, which remains the leading cause of death from gynecologic cancer. Several studies have shown that the antiapoptotic proteins Bcl-xL and Mcl-1, as well as the proapoptotic protein Bim, are key elements to be modulated to kill ovarian cancer cells. Pharmacologic inhibition of Bcl-xL is possible by using BH3-mimetic molecules like ABT-737. However, inhibition of Mcl-1 and/or promotion of its BH3-only partners (including Bim, Puma, and Noxa) remains a challenge that may be achieved by modulating the signaling pathways upstream. This study sought whether AZD8055-induced mTOR inhibition and/or trametinib-induced MEK inhibition could modulate Mcl-1 and its partners to decrease the Mcl-1/BH3-only ratio and thus sensitize various ovarian cancer cell lines to ABT-737. AZD8055 treatment inhibited Mcl-1 and increased Puma expression but did not induce massive apoptosis in combination with ABT-737. In contrast, trametinib, which decreased the Mcl-1/BH3-only protein ratio by upregulating Puma and dephosphorylated active Bim, sensitized IGROV1-R10 and OVCAR3 cells to ABT-737. Adding AZD8055 to trametinib further reduced the Mcl-1/BH3-only protein ratio and triggered apoptosis without ABT-737 in IGROV1-R10 cells. Moreover, the AZD8055/trametinib association highly sensitized all cell lines including SKOV3 to ABT-737, the induced dephosphorylated Bim being crucial in this sensitization. Finally, the three-drug combination was also very efficient when replacing AZD8055 by the pan-Akt inhibitor MK-2206. This study thus proposes original multitargeted strategies and may have important implications for the design of novel approaches for ovarian cancer treatment. Mol Cancer Ther; 16(1); 102-15. (c)2016 AACR.
Delineating the mTOR kinase pathway using a dual TORC1/2 inhibitor, AZD8055, in multiple myeloma.[Pubmed:25172964]
Mol Cancer Ther. 2014 Nov;13(11):2489-500.
Despite promising preclinical results with mTOR kinase inhibitors in multiple myeloma, resistance to these drugs may arise via feedback activation loops. This concern is especially true for insulin-like growth factor 1 receptor (IGF1R), because IGF1R signaling is downregulated by multiple AKT and mTOR feedback mechanisms. We have tested this hypothesis in multiple myeloma using the novel selective mTOR kinase inhibitor AZD8055. We evaluated p-mTOR S(2481) as the readout for mTORC2/Akt activity in multiple myeloma cells in the context of mTOR inhibition via AZD8055 or rapamycin. We next validated AZD8055 inhibition of mTORC1 and mTORC2 functions in multiple myeloma cells alone or in culture with bone marrow stroma cells and growth factors. Unlike rapamycin, AZD8055 resulted in apoptosis of multiple myeloma cells. AZD8055 treatment, however, induced upregulation of IGF1R phosphorylation in p-Akt S(473)-expressing multiple myeloma cell lines. Furthermore, exposure of AZD8055-treated cells to IGF1 induced p-Akt S(473) and rescued multiple myeloma cells from apoptosis despite mTOR kinase inhibition and TORC2/Akt blockage. The addition of blocking IGF1R antibody resulted in reversing this effect and increased AZD8055-induced apoptosis. Our study suggests that combination treatment with AZD8055 and IGF1R-blocking agents is a promising strategy in multiple myeloma with potential IGF1R/Akt signaling-mediated survival.