Molecular Weight (MW)

462.54

Formula

C25H30N6O3

CAS No.

1009298-59-2

Storage

-20℃ for 3 years in powder form

-80℃ for 2 years in solvent

Solubility (In vitro)

DMSO: 38 mg/mL (82.15 mM)

Water: <1 mg/mL

Ethanol: <1 mg/mL

Solubility (In vivo)

5% DMSO+30% PEG 300+ddH2O: 5mg/mL

Synonyms

AZD2014, AZD-2014, AZD 2014; 3-[2,4-Bis((3S)-3-methylmorpholin-4-yl)pyrido[5,6-e]pyrimidin-7-yl]-N-methylbenzamide; Vistusertib

Chemical Name: 3-[2,4-Bis((3S)-3-methylmorpholin-4-yl)pyrido[5,6-e]pyrimidin-7-yl]-N-methylbenzamide

InChi Key: JUSFANSTBFGBAF-IRXDYDNUSA-N

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

SMILES Code: O=C(NC)C1=CC=CC(C2=CC=C3C(N4[C@@H](C)COCC4)=NC(N5[C@@H](C)COCC5)=NC3=N2)=C1

In Vitro

Kinase Assay: Vistusertib (also known as AZD2014) is a novel, oral mTOR inhibitor with IC50 of 2.8 nM in a cell-free assay; it is highly 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.

In Vivo

AZD2014 induces tumour growth inhibition against several xenograft models including a human primary explant model of ER+ breast cancer refractory to tamoxifen. The antitumour activity is associated with modulation of both mTORC1 and mTORC2 substrates.

Animal model

Mice

Formulation & Dosage

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). Vistusertib (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

Bioorg Med Chem Lett. 2013 Mar 1;23(5):1212-6; Oncotarget. 2014 Jul 15;5(13):4990-5001.