Background
Target: ALK, IGF1R
IC50: 0.75 nM(Ki)
AZD3463 is a novel orally bioavailable ALK/IGF1R inhibitor with Ki value of 0.75 nM. ALK expression is largely restricted to neurons and upregulated in neuroblastoma. Activated ALK has been shown to promote cell survival and growth. High ALK expression or mutations in the ALK gene correlates with adverse outcomes in neuroblastoma. Therefore, ALK receptor tyrosine kinase is an important therapeutic target for drug development against neuroblastoma [1].
In vitro: AZD3463 (5, 10, 20, and 50 μM) effectively inhibited the proliferation of neuroblastoma cell lines with wild type ALK (WT) and ALK activating mutations (F1174L and D1091N) via targeting the ALK-mediated PI3K/AKT/mTOR pathway and ultimately induced apoptosis and autophagy in vitro. Moreover, AZD3463 (1 μM) significantly enhanced the cytotoxic effects of doxorubicin (1 μM) on neuroblastoma cells [1]. AZD3463 simultaneously inhibited STAT3 and AKT to augment the cytotoxic effects of temozolomide and further reduce cell growth [2].
In vivo: AZD3463 (15 mg/kg, i.p. injection) showed significant therapeutic efficacy on the growth of the neuroblastoma tumors with WT and F1174L oncogenic mutant ALK in orthotopic xenograft mouse models [1].
参考文献:
1.? Wang Y, Wang L, Guan S, Cao W, Wang H, Chen Z, et al. Novel ALK inhibitor AZD3463 inhibits neuroblastoma growth by overcoming crizotinib resistance and inducing apoptosis. Sci Rep. 2016;6:19423.
2.? Sampson VB, Vetter NS, Kamara DF, Collier AB, Gresh RC, Kolb EA. Vorinostat Enhances Cytotoxicity of SN-38 and Temozolomide in Ewing Sarcoma Cells and Activates STAT3/AKT/MAPK Pathways. PLoS One. 2015;10(11):e0142704.
Protocol
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Cell experiment [1]:
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Cell lines
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ALK wild type cell lines (SK-N-AS, IMR-32, NGP, NB-19) and ALK mutant cell lines (LA-N-6 (D1091N) and SH-SY5Y (WT/F1174L))
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Preparation method
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The solubility of this compound in DMSO is >11.2mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.
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Reacting condition
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0~50 μM, 72h
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Applications
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AZD-3463 effectively suppressed the proliferation of neuroblastoma cell lines with wild type ALK as well as ALK activating mutations by blocking the ALK-mediated PI3K/AKT/mTOR pathway and ultimately induced apoptosis and autophagy.
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Animal experiment [1]:
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Animal models
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Orthotopic Neuroblastoma Mouse Model
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Dosage form
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15 mg/kg intraperitoneal injection once daily for 2 days.
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Application
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AZD-3463 exhibited significant therapeutic efficacy on the growth of the neuroblastoma tumors with WT and F1174L activating mutation ALK in orthotopic xenograft mouse models.
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Other notes
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Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
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参考文献:
[1] Wang Y, Wang L, Guan S, Cao W, Wang H, Chen Z, et al. Novel ALK inhibitor AZD3463 inhibits neuroblastoma growth by overcoming crizotinib resistance and inducing apoptosis. Sci Rep. 2016;6:19423.
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