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Purity: ≥98%
Vistusertib (formerly AZD-2014) is a novel, potent, orally bioavailable and ATP competitive inhibitor of mTOR (mammalian target of rapamycin) with potential antitumor activity. IIt exhibits high selectivity for PI3K α/β/γ/δ and inhibits mTOR with an IC50 of 2.8 nM in a cell-free assay.
| Targets |
mTOR (IC50 = 2.81 nM); PI3Kα (IC50 = 3.766 μM); mTORC1; mTORC2; Autophagy
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|---|---|
| ln Vitro |
AZD2014 is a close analogue of AZD8055 and a selective inhibitor of mTOR kinase. AZD2014 inhibits the translation initiation complex, p4EBP1 Thr37/46, and overall protein synthesis while rapamycin has no effect on any of these. This indicates that AZD2014 has greater inhibitory activity against mTORC1 than rapamycin. The biomarkers pNDRG1Thr346 and pAKTSer473 of mTORC2 are also inhibited by AZD2014. Numerous tumor cell lines are responsive to AZD2014's broad antiproliferative activity. In particular, AZD2014 causes cell death and growth inhibition in breast cancer cell lines, including ER+ cell lines that have developed resistance to hormone therapy.[1]
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| ln Vivo |
AZD2014 induces tumour growth inhibition against several xenograft models including a human primary explant model of ER+ breast cancer refractory to tamoxifen. Modulation of the substrates for mTORC1 and mTORC2 is linked to the antitumor activity. [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. In combination with fulvestrant, AZD2014 induces tumor regressions when dosed continuously or using intermittent dosing schedules. The ability to dose AZD2014 intermittently, together with its ability to block signaling from both mTORC1 and mTORC2 complexes, makes this compound an ideal candidate for combining with endocrine therapies in the clinic. AZD2014 is currently in phase II clinical trials.[2] |
| Enzyme Assay |
Enzyme assays[2]
Recombinant truncated FLAG-tagged mTOR (aa1362-2549) expressed in HEK 293 cells was used in biochemical assays, together with a biotinylated p70S6K peptide substrate. Streptavidin donor and protein A acceptor beads were used to assemble the capture complex for generation of the assay signal. The activity of the lipid kinases, PI3 kinase alpha, beta, delta, and gamma were measured using recombinant proteins and the lipid PIP2 as substrate. Assays for ATM and DNA-PK activity were performed as described previously. The selectivity of AZD2014 was tested against kinase panels from Dundee, Millipore and Ambit. mTOR cellular activity was measured in MDAMB468 cells, using an Acumen laser scanning cytometer to analyze the levels of phosphorylation of S6 (Ser235/236) and AKT (Ser473). Vistusertib (also known as AZD2014)is a novel, oralmTOR inhibitor with IC50 of 2.8 nM in a cell-free assay; it ishighly selective against multiple PI3K isoforms (α/β/γ/δ). |
| Cell Assay |
AZD2014 is a close analogue of AZD8055 and a selective inhibitor of mTOR kinase. AZD2014 has greater inhibitory activity against mTORC1 compared to rapamycin: AZD2014 decreases p4EBP1 Thr37/46, inhibits the translation initiation complex and decreases overall protein synthesis while rapamycin has no effect. AZD2014 also inhibits the mTORC2 biomarkers pAKTSer473 and pNDRG1Thr346. AZD2014 has broad antiproliferative activity across multiple tumour cell lines. In particular, AZD2014 induces growth inhibition and cell death in breast cancer cell lines, including ER+ cell lines with acquired resistance to hormone therapy.
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| Animal Protocol |
Mice; 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. Vistusertib (AZD2014) is dissolved in captisol, and diluted to a final captisol concentration of 30% (w/v). Oral gavage (0.1 mL/10 g of body weight) is used to administer vistusertib (AZD2014). The control group only receives vehicles. For the duration of the study, tumor volumes (calculated using a calliper), animal body weight, and condition are recorded twice a week. 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).
Plasma pharmacokinetic analysis Blood samples were taken from mice following administration of AZD2014 and plasma prepared by centrifugation. The concentration of AZD2014 in the plasma samples was determined using a protein precipitation extraction procedure, followed by LC/MS-MS detection using Masslynx and processed using Quanlynx.[2] |
| ADME/Pharmacokinetics |
The pharmacokinetics of AZD2014 in mice was tested upon administration of doses between 7.5 and 15 mg/kg. A dose-dependent increase in Cmax and AUC was observed following single dose and repeat dosing of AZD2014: Cmax ranged from 1 to 16 μmol/L and AUC ranged from 220 to 5,042 μmol/L·h across this dose range (Supplementary Fig. S2A). The pharmacodynamic effect of AZD2014 against an mTORC1 biomarker (phosphorylation of S6) and an mTORC2 biomarker (phosphorylation of AKT) was assessed in SCID mice bearing MCF7 xenografts following administration of 3.75, 7.5, and 15 mg/kg AZD2014. There was a good relationship between the drug plasma concentrations and biomarker levels (estimated p-AKT IC50 of 0.119 μmol/L total, 53% SE, Supplementary Fig. S[2]
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| References | |
| Additional Infomation |
Vistusertib is under investigation for the treatment of Advanced Gastric Adenocarcinoma.
Vistusertib is an orally bioavailable inhibitor of the mammalian target of rapamycin (mTOR) with potential antineoplastic activity. Vistusertib inhibits the activity of mTOR, which may result in the induction of tumor cell apoptosis and a decrease in tumor cell proliferation. mTOR, a serine/threonine kinase that is upregulated in a variety of tumors, plays an important role downstream in the PI3K/Akt/mTOR signaling pathway. |
| Molecular Formula |
C25H30N6O3
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|---|---|
| Molecular Weight |
462.5441
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| Exact Mass |
462.237
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| Elemental Analysis |
C, 64.92; H, 6.54; N, 18.17; O, 10.38
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| CAS # |
1009298-59-2
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| Related CAS # |
1009298-59-2
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| PubChem CID |
25262792
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| Appearance |
Yellow solid powder
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| Density |
1.2±0.1 g/cm3
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| Index of Refraction |
1.607
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| LogP |
0.28
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
4
|
| Heavy Atom Count |
34
|
| Complexity |
698
|
| Defined Atom Stereocenter Count |
2
|
| SMILES |
O1C([H])([H])C([H])([H])N(C2C3C([H])=C([H])C(C4C([H])=C([H])C([H])=C(C(N([H])C([H])([H])[H])=O)C=4[H])=NC=3N=C(N=2)N2C([H])([H])C([H])([H])OC([H])([H])[C@]2([H])C([H])([H])[H])[C@@]([H])(C([H])([H])[H])C1([H])[H]
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| InChi Key |
JUSFANSTBFGBAF-IRXDYDNUSA-N
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| InChi Code |
InChI=1S/C25H30N6O3/c1-16-14-33-11-9-30(16)23-20-7-8-21(18-5-4-6-19(13-18)24(32)26-3)27-22(20)28-25(29-23)31-10-12-34-15-17(31)2/h4-8,13,16-17H,9-12,14-15H2,1-3H3,(H,26,32)/t16-,17-/m0/s1
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| Chemical Name |
3-[2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-N-methylbenzamide
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| Synonyms |
Vistusertib; AZD2014; AZD-2014; Vistusertib [INN]; AZD 2014; 3-[2,4-Bis((3S)-3-methylmorpholin-4-yl)pyrido[5,6-e]pyrimidin-7-yl]-N-methylbenzamide; Vistusertib (AZD-2014); AZD 2014; AZD-2014
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
DMSO: ~38 mg/mL (~82.2 mM)
Water: <1 mg/mL Ethanol: <1 mg/mL |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.40 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.5 mg/mL (5.40 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with heating and sonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: 2.5 mg/mL (5.40 mM) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Solubility in Formulation 4: 2.5 mg/mL (5.40 mM) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 5: 5% DMSO+30% PEG 300+ddH2O: 5mg/mL |
| Preparing Stock Solutions | 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 |
*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.
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.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Status | Interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03071874 | Active Recruiting |
Drug: AZD2014 | Meningioma | Massachusetts General Hospital | October 17, 2017 | Phase 2 |
| NCT02664935 | Active Recruiting |
Drug: AZD4547 Drug: Vistusertib |
Adenocarcinoma Non-Small Cell Lung Cancer |
University of Birmingham | May 2015 | Phase 2 |
| NCT02599714 | Active Recruiting |
Drug: AZD2014 Drug: Palbociclib |
Advanced and Metastatic Breast Cancer |
AstraZeneca | December 7, 2015 | Phase 1 |
| NCT02208375 | Active Recruiting |
Drug: Vistusertib Drug: Olaparib |
HER2/Neu Negative BRCA2 Mutation Carrier |
M.D. Anderson Cancer Center | November 11, 2014 | Phase 1 Phase 2 |
Oncotarget. 2014 Jul 15;5(13):4990-5001. |
Oncotarget. 2014 Jul 15;5(13):4990-5001. |
Oncotarget. 2014 Jul 15;5(13):4990-5001. |
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