1. PI3K/Akt/mTOR
    Autophagy
  2. mTOR
    Autophagy

AZD2014 (Synonyms: Vistusertib; AZD-2014)

Cat. No.: HY-15247 Purity: 98.99%
Handling Instructions

AZD2014 is a small-molecule ATP competitive mTOR inhibitor with IC50 of 2.81 nM.

For research use only. We do not sell to patients.
AZD2014 Chemical Structure

AZD2014 Chemical Structure

CAS No. : 1009298-59-2

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10 mM * 1 mL in DMSO $77 In-stock
5 mg $70 In-stock
10 mg $120 In-stock
50 mg $250 In-stock
100 mg $400 In-stock
200 mg $750 In-stock
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  • Biological Activity

  • Protocol

  • Technical Information

  • Purity & Documentation

  • References

Description

AZD2014 is a small-molecule ATP competitive mTOR inhibitor with IC50 of 2.81 nM.

IC50 & Target

IC50: 2.81 nM (mTOR)[1]

In Vitro

The inhibitory effects of AZD2014 are measured against isolated recombinant mTOR enzyme (IC50 of 2.81 nM) as well as in cellular assays measuring both mTORC1 and mTORC2 activities. In MDAMB468 cells, AZD2014 decreases the phosphorylation of the mTORC1 substrate ribosomal protein S6 (Ser235/236) with a mean IC50 value of 210 nM and the mTORC2 substrate AKT (Ser473) with a mean IC50 value of 78 nM[1].

In Vivo

AZD2014 induces dose-dependent tumor growth inhibition in several xenograft and primary explant models. The antitumor activity of AZD2014 is associated with modulation of both mTORC1 and mTORC2 substrates, consistent with its mechanism of action. The pharmacokinetics of AZD2014 in mice is tested upon administration of doses between 7.5 and 15 mg/kg. A dose-dependent increase in Cmax and AUC is observed following single dose and repeat dosing of AZD2014: Cmax range from 1 to 16 μM and AUC range from 220 to 5,042 μM•h across this dose range. The pharmacodynamic effect of AZD2014 against an mTORC1 biomarker (phosphorylation of S6) and an mTORC2 biomarker (phosphorylation of AKT) is assessed in SCID mice bearing MCF7 xenografts following administration of 3.75, 7.5, and 15 mg/kg AZD2014. There is a good relationship between the drug plasma concentrations and biomarker levels (estimated p-AKT IC50 of 0.119 μM total, 53% SE, and estimated p-S6 IC50 0.392 μM, 28.8% SE)[1].

Clinical Trial
Sponsor Condition Start Date Phase
Queen Mary University of London Metastatic renal cancer 2013-02-28 Phase 2
AstraZeneca plc Metastatic breast cancer 2012-05-31 Phase 1
Daiichi Sankyo Inc Advanced solid tumor 2012-04-30 Phase 1
AstraZeneca plc Advanced solid tumor 2009-12-31 Phase 1
References
Preparing Stock Solutions
Concentration Volume (DMSO) Mass 1 mg 5 mg 10 mg
1 mM 2.1620 mL 10.8099 mL 21.6198 mL
5 mM 0.4324 mL 2.1620 mL 4.3240 mL
10 mM 0.2162 mL 1.0810 mL 2.1620 mL
Kinase Assay
[1]

Recombinant truncated FLAG-tagged mTOR expressed in HEK 293 cells is used in biochemical assays, together with a biotinylated p70S6K peptide substrate. Streptavidin donor and protein A acceptor beads are used to assemble the capture complex for generation of the assay signal. The activity of the lipid kinases, PI3K alpha, beta, delta, and gamma are measured using recombinant proteins and the lipid PIP2 as substrate. Assays for ATM and DNA-PK activity are performed. The mTOR cellular activity is measured in MDAMB468 cells, using an Acumen laser scanning cytometer to analyze the levels of phosphorylation of S6 (Ser235/236) and AKT (Ser473)[1].

Cell Assay
[1]

AZD2014 is prepared in DMSO (10 mM) and stored under nitrogen, and then diluted with appropriate media before use[1].

Cells are plated in 96-well plates for the indicated time. For CellTiterGlo assays: CellTiterGlo is mixed with the cells. Cells are normalized to day 0 control and net growth is determined using the following formula: ((x−y)/(z−y))=net growth, where x=reading of treated sample at end of study, y=average reading on day 0, and z=reading of DMSO-treated sample at end of study. The concentration of DMSO does not exceed 0.03% for any experiment. For MTS assays: adherent cell lines are grown in 96-well plates. MTS reagent is added on day 0 and on day 3 post-AZD2014 addition. Suspension lines are assayed using the Alamar Blue reagent, 72 hours after AZD2014 addition[1].

Animal Administration
[1]

AZD2014 is dissolved in captisol, and diluted to a final captisol concentration of 30% (w/v) (Mice)[1].

Mice[1]
MCF7 experiments: 5×106 MCF7 cells are injected s.c. in a volume of 0.1 mL in male SCID mice and are randomized into control and treatment groups when tumor size reach 0.2 cm3. AZD2014 is dissolved in captisol, and diluted to a final captisol concentration of 30% (w/v). AZD2014 is administered by oral gavage (0.1 mL/10 g body weight). The control group receive vehicle only. Tumor volumes (measured by calliper), animal body weight and condition are recorded twice weekly for the duration of the study. The tumor volume is calculated (taking length to be the longest diameter across and width to be the corresponding perpendicular diameter) using the formula: (length×width)×√(length×width)×(π/6).

References
M.Wt

462.54

Formula

C₂₅H₃₀N₆O₃

CAS No.

1009298-59-2

Storage
Powder -20°C 3 years
  4°C 2 years
In solvent -80°C 6 months
  -20°C 1 month
Shipping

Room temperature in continental US; may vary elsewhere

Solvent & Solubility

10 mM in DMSO

Purity: 98.99%

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AZD2014
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