AZD8055

Alias:

AZD8055; AZD-8055; AZD 8055

Cat No.:V0177 Purity: ≥98%
AZD8055 is a novel, potent selective, and orally bioavailableATP-competitive mTOR (mammalian target of rapamycin) inhibitor with potential anticancer activity.
AZD8055 Chemical Structure CAS No.: 1009298-09-2
Product category: mTOR
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

AZD8055 is a novel, potent selective, and orally bioavailable ATP-competitive mTOR (mammalian target of rapamycin) inhibitor with potential anticancer activity. It has excellent selectivity (∼1,000-fold) against PI3K isoforms and ATM/DNA-PK and inhibits mTOR with an IC50 of 0.8 nM in MDA-MB-468 cells. In its role as an mTOR inhibitor, AZD-8055 demonstrated strong anti-tumor activity by preventing mTOR's serine/threonine kinase activity. This decreased expression of mRNAs required for cell cycle progression may result in cell cycle arrest and tumor cell apoptosis. Transcriptional factors phosphorylated by mTOR include S6K1 and 4E-BP1, which promote protein synthesis and control cell growth, proliferation, motility, and survival.

Biological Activity I Assay Protocols (From Reference)
Targets
mTOR (IC50 = 0.13 nM); mTOR (IC50 = 0.8 nM)
ln Vitro
AZD8055 shows low activity (∼1,000-fold) against all PI3K isoforms (α, β, γ, δ) and other members of the PI3K-like kinase family (ATM and DNA-PK). AZD8055 prevents the phosphorylation of mTORC1 (p70S6K and 4E-BP1), mTORC2 (Akt), and downstream proteins. A significant amount of cap-dependent translation can be inhibited by AZD8055 because it completely inhibits the rapamycin-resistant T37/46 phosphorylation sites on 4E-BP1. With IC50 values of 53, 50, and 20 nM, respectively, AZD8055 potently inhibits proliferation in U87MG, A549, and H838 cells. In addition, autophagy and elevated LC3-II levels are induced by AZD8055 in H838 and A549 cells.[1] AML blast cell proliferation and cell cycle progression are reduced, leukemic progenitors' clonogenic growth is inhibited, and AZD8055 induces caspase-dependent apoptosis in leukemic cells but not in healthy, immature CD34+ cells.[2] With an IC50 of 24.7 nM, AZD8055 exhibits inhibitory activity against the pediatric preclinical testing program (PPTP) cell lines and causes appreciable variations in EFS distribution. [3]
ln Vivo
AZD8055 inhibits the pS6 and pAkt in U87MG and A549 xenografts at 2.5/10 mg/kg, which leads to tumor growth inhibition. At doses of 10–20 mg/kg, AZD8055 significantly inhibits tumor growth in a variety of xenografts, including U87MG, BT474c, A549, Calu-3, LoVo, SW620, PC3, and MES-SA. [1] A 40% reduction in tumor volume is brought about by AZD8055, and Akt, S6K, and SGK protein kinase phosphorylation are also eliminated. By inhibiting mTORC1 and mTORC2 signaling, the administration of AZD8055 (5 mg/kg, Bid) and SAHA (100 mg/kg/d) completely inhibits tumor growth in PTEN+/−LKB1+/hypo xenografts in mice. [4]
Enzyme Assay
In order to identify mTORC1 and mTORC2 activity, a high-throughput screening cell-based assay is created using MDA-MB-468 cells. Increasing amounts of AZD8055 are applied to cells for two hours. Cells are fixed, cleaned, and then probed with S473 pAkt or S235/236 phosphorylated S6 (pS6) antibodies at the conclusion of the incubation period. Utilizing an Acumen laser scanning cytometer, phosphorylation levels are measured. cells to detect mTORC1 and mTORC2 activity. Cells are exposed for 2 hours to increasing concentrations of AZD8055. At the end of the incubation period, cells are fixed, washed, and probed with antibodies against S473 pAkt or against S235/236 phosphorylated S6 (pS6). Levels of phosphorylation are assessed using an Acumen laser scanning cytometer.
Cell Assay
Cell nuclei are stained for (0.03 mg/mL Hoechst 33342) and acidic vesicles (1 g/mL acridine orange) in cells that have been exposed to AZD8055 for 72 to 96 hours. On an ArrayScan II platform, images are taken at 450 and 536 nm, and the proportion of acidic vesicles and the number of cells are counted. Before being incubated with AZD8055, cells are exposed to e64d/pepstatin (10 g/mL) for 30 to 90 min in order to assess LC3. After being lysed on ice, cells are examined using immunoblotting.
Animal Protocol
U87MG, BT474c, A549, Calu-3, LoVo, SW620, PC3 and MES-SA U87-MG and A549 are established in pathogen-free, female nude mice (nu/nu:Alpk).
2.5-20 mg/kg
Oral gavage once or twice daily
References

[1]. Cancer Res . 2010 Jan 1;70(1):288-98.

[2]. Leukemia . 2012 Jun;26(6):1195-202.

[3]. Pediatr Blood Cancer . 2012 Feb;58(2):191-9.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C25H31N5O4
Molecular Weight
465.5447
Exact Mass
465.2376
Elemental Analysis
C, 64.50; H, 6.71; N, 15.04; O, 13.75
CAS #
1009298-09-2
Appearance
Yellow solid powder
SMILES
C[C@H]1COCCN1C2=NC(=NC3=C2C=CC(=N3)C4=CC(=C(C=C4)OC)CO)N5CCOC[C@@H]5C
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
Chemical Name
[5-[2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2-methoxyphenyl]methanol
Synonyms

AZD8055; AZD-8055; AZD 8055

HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: ~50 mg/mL (~107.4 mM)
Water: <1 mg/mL
Ethanol: ~3 mg/mL (~6.4 mM)
Solubility (In Vivo)
4% DMSO+30% PEG 300+ddH2O: 5mg/mL (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 2.1480 mL 10.7402 mL 21.4804 mL
5 mM 0.4296 mL 2.1480 mL 4.2961 mL
10 mM 0.2148 mL 1.0740 mL 2.1480 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

Calculator

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Note: Chemical formula is case sensitive: C12H18N3O4  c12h18n3o4
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In vivo Formulation Calculator (Clear solution)
Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)
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Calculation results

Working concentration mg/mL;

Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.

(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
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Clinical Trial Information
NCT Number Status Interventions Conditions Sponsor/Collaborators Start Date Phases
NCT01316809 Completed Drug: AZD8055 Malignant Glioma
Brainstem Glioma
National Cancer Institute
(NCI)
March 4, 2011 Phase 1
NCT00973076 Completed Drug: AZD8055 Cancer
Solid Tumors
AstraZeneca August 2009 Phase 1
NCT00999882 Completed Drug: AZD8055 Cancer
Advanced Hepatocellular
Carcinoma
AstraZeneca October 2009 Phase 1
NCT00731263 Completed Drug: AZD8055 Solid Tumors AstraZeneca July 2008 Phase 1
Biological Data
  • AZD8055

  • AZD8055
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