The kinase mTOR, belonging to the PIKKs family, which regulate cell growth, cell survival, and autophagy, is a key target in the development of antitumor therapies. It was found that rapamycin and its analogues, the first generation of mtor inhibitor, can activate AKT signaling as a consequence of inhibition of the negative feedback loop downstream of mTORC1. AZD2014 (Vistusertib) is a potent mTORC1/2 inhibitor (IC50 = 2.8 nM, measured by recombinant truncated FLAG-tagged mTOR) and displays a high level of selectivity against other members of the PIKKs [a]. Different from rapamycin, treatment with AZD2014 at 3 to 1000 nM can significantly inhibit mTOR substrates, such as pS6-S235/236, p70S6K-T389 and 4E-BP1 Thr37/46, in a dose dependent manner, as well as no AKT activation, in MCF7 cells. While effectively inhibiting signaling to S6, PRAS40 as well as feedback phosphorylation of AKT, AZD2014 can block proliferation in all cell lines, including everolimus-resistant cells and long-term estrogen-deprived (LTED) everolimus-resistant cells at concentration 200/500 nM. Treatment of 15 mg/kg AZD2014 can induce significant growth inhibition in several hormone therapy–sensitive ERb breast cancer xenograft models like MCF7 and HCC1500, as well as three patient-derived primary explant models BR0555, CTC174, and HBCx3. Up to now, AZD2014 enters Phase 1 trial in solid tumours[1].
作用机制
AZD2014 is a small-molecule ATP competitive inhibitor of mTOR[2]
Vistusertib 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Vero kidney epithelial cells
25 nM
72 h
Reduced SARS-CoV-2 replication
Nat Commun. 2021 Mar 25;12(1):1876.
GL261 cells
250 nM
72 h
To evaluate the synergistic effect of Vistusertib with BET inhibitor Birabresib, the results showed that the combination of Vistusertib and Birabresib had potential synergy.
EBioMedicine. 2023 Sep;95:104752.
MPM/AF 3D co-culture spheroids
10 µM
72 h
To test the single-agent efficacy of Vistusertib in MPM/AF 3D co-culture spheroids, results showed its efficacy was superior to the cisplatin/pemetrexed combination.
Cell Death Dis. 2023 Nov 8;14(11):725.
MCF7
20 nM
72 h
To evaluate the effect of Vistusertib on the proliferation of MCF7 cells, results showed a concentration-dependent decrease in proliferation in the presence of E2.
Breast Cancer Res. 2019 Dec 4;21(1):135.
MCF7 LTEDY537C
50 nM
72 h
To evaluate the effect of Vistusertib on the proliferation of MCF7 LTEDY537C cells, results showed sensitivity in both the presence and absence of E2.
Breast Cancer Res. 2019 Dec 4;21(1):135.
MCF7 LTEDwt
75 nM
72 h
To evaluate the effect of Vistusertib on the proliferation of MCF7 LTEDwt cells, results showed a concentration-dependent decrease in proliferation.
Breast Cancer Res. 2019 Dec 4;21(1):135.
MCF7 TAMR
85 nM
72 h
To evaluate the effect of Vistusertib on the proliferation of MCF7 TAMR cells, results showed a concentration-dependent decrease in proliferation.
Breast Cancer Res. 2019 Dec 4;21(1):135.
MCF7 ICIR
50 nM
72 h
To evaluate the effect of Vistusertib on the proliferation of MCF7 ICIR cells, results showed a concentration-dependent decrease in proliferation.
Breast Cancer Res. 2019 Dec 4;21(1):135.
Vistusertib 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Nf2/Bap1/Cdkn2a triple-floxed mice
Intraperitoneal injection
15 mg/kg
3 weeks (7 days on, 2 days off, 5 days on, 2 days off, 5 days on)
To test the efficacy of Vistusertib as a single agent in a mouse model, results showed it did not significantly improve survival.
Cell Death Dis. 2023 Nov 8;14(11):725.
Mice
HBCx34 OvaR PDX model
Oral gavage
15 mg/kg
Daily for 90 days
To evaluate the effect of Vistusertib alone or in combination with Fulvestrant on tumour progression in the HBCx34 OvaR PDX model, results showed that Vistusertib alone or in combination with Fulvestrant significantly inhibited tumour progression.
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