AZD8055

 

Distributor Tel: +886-2-2827-1197jimmy@new.abscience.com.tw

Biological Activity

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. Phase 1.
Targets	mTOR (full length)	mTOR (truncated)
IC50	0.8 nM	0.13 nM [1]
In 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 inhibits the phosphorylation of mTORC1 (p70S6K and 4E-BP1) as well as phosphorylation of the mTORC2 (Akt) and downstream proteins. The rapamycin-resistant T37/46 phosphorylation sites on 4E-BP1 can be fully inhibited by AZD8055, resulting in significant inhibition of cap-dependent translation. AZD8055 potently inhibits proliferation in U87MG, A549 and H838 cells with IC50 of 53, 50 and 20 nM, respectively. AZD8055 also induces autophagy and increased LC3-II levels in H838 and A549 cells. [1] AZD8055 decreases AML blast cell proliferation and cell cycle progression, reduces the clonogenic growth of leukemic progenitors and induces caspase-dependent apoptosis in leukemic cells but not in normal immature CD34+ cells. [2] AZD8055 indicates inhibitory against the pediatric preclinical testing program (PPTP) cell lines with IC50 of 24.7 nM and induces significant differences in EFS distribution. [3]
In vivo	AZD8055 inhibits the pS6 and pAkt in U87MG and A549 xenografts at 2.5/10 mg/kg, which leads to tumor growth inhibition. AZD8055 shows significant antitumor activity in many xenografts, including U87MG, BT474c, A549, Calu-3, LoVo, SW620, PC3 and MES-SA at a dose of 10/20 mg/kg. [1] AZD8055 induces ~40% reduction in tumour volume, accompanied by ablation of phosphorylation of Akt, S6K and SGK protein kinases. Administration of AZD8055 (5mg/kg, Bid) and SAHA (100 mg/kg/d) results in complete tumor growth inhibition in PTEN+/−LKB1+/hypo xenografts without side effects on mice by inhibition of mTORC1 and mTORC2 signaling. [4]
Features	First drug to inhibit both types of mTOR protein.

Protocol(Only for Reference)

Kinase Assay: ^[1]

Cell-based determinations of mTOR inhibition

A high-throughput screening cell-based assay is developed using MDA-MB-468 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: ^[1]

Cell lines	U87MG, A549 and H838 cells
Concentrations	1 nM - 1 μM
Incubation Time	72 to 96 hours
Method	Cells are exposed to AZD8055 for 72 to 96 hours and stained for cell nuclei (0.03 mg/mL Hoechst 33342) and acidic vesicles (1 μg/mL acridine orange). Images are captured at 450 and 536 nm on an ArrayScan II platform, and the percentage of acidic vesicles and the number of cells are quantified. For LC3 assessment, cells are exposed to e64d/pepstatin (10 μg/mL) for 30 to 90 min before incubation with AZD8055. Cells are lysed on ice and analyzed by immunoblotting.

Animal Study: ^[1]

Animal Models	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).
Dosages	2.5-20 mg/kg
Administration	Oral gavage once or twice daily

1

References

Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number	Recruitment	Conditions	Sponsor /Collaborators	Start Date	Phases
NCT01194193	Withdrawn	Cancer|Advanced Solid Tumours|Lymphomas	AstraZeneca		Phase 1
NCT00731263	Completed	Solid Tumors	AstraZeneca	2008-07	Phase 1
NCT00973076	Completed	Cancer|Solid Tumors|Advanced Solid Malignancies	AstraZeneca	2009-08	Phase 1
NCT00999882	Completed	Cancer|Advanced Hepatocellular Carcinoma	AstraZeneca	2009-10	Phase 1
NCT01316809	Active, not recruiting	Glioblastoma Multiforme|Anaplastic Astrocytoma|Anaplastic Oligodendroglioma|Malignant Glioma|Brainstem Glioma	National Institutes of Health Clinical Center (CC)|National Cancer Institute (NCI)	2011-03	Phase 1

Chemical Information

Download AZD8055 SDF

Chemical Name	(5-(2,4-bis((S)-3-methylmorpholino)pyrido[2,3-d]pyrimidin-7-yl)-2-methoxyphenyl)methanol

Preparing Stock Solutions

Stock Solution (1ml DMSO)	1mM	10mM	20mM	30mM
Mass(mg)	0.46554	4.6554	9.3108	13.9662

Customer Reviews (2)

Click to enlarge	Rating
	Source	Exp Neurol 2012 233, 799-806. AZD8055 purchased from Selleck
	Method	Western blotting
	Cell Lines	basilar artery
	Concentrations
	Incubation Time
	Results	Treatment with Rapamycin and AZD8055 significantly suppressed the expression of mTOR, P70S6K1, 4E-BP1, and PCNA.

Product Citations (12)

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  Computational model for autophagic vesicle dynamics in single cells. [Martin KR, et al. Autophagy 2012;9(1):74-92]

  
  PubMed: 23196898


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  PTEN phosphorylation and nuclear export mediate free fatty acid-induced oxidative stress. [Wu Y, et al. Antioxid Redox Signal 2013;10.1089/ars.2013.5498]

  
  PubMed: 24063548


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  Prevention of BMS-777607-induced polyploidy/senescence by mTOR inhibitor AZD8055 sensitizes breast cancer cells to cytotoxic chemotherapeutics [Sharad Sharma, et al. Molecular Oncology 2013;10.1016/j.molonc.2013.12.014]

  
  PubMed: 24444656