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].

References:
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.