ALK (anaplastic lymphoma kinase) is a tyrosine kinase that is constitutively activated in certain cancers, following gene alterations such as chromosomal translocation, amplification or point mutation. The fusion protein NPM-ALK, which is generated from a hybrid gene consisting of the intracellular domain of the ALK tyrosine kinase receptor juxtaposed with nucleophosmin, has constitutive tyrosine kinase activity and is associated with 50–60% of cases of anaplastic large-cell lymphomas. NVP-TAE 684 is a potent and selective NPM-ALK kinase inhibitor without exhibiting significant cross-reactivity against other kinases tested, including the highly homologous InsR. Consistent with this, NVP-TAE 684 exhibited inhibitory concentrations (IC50) between 2 and 5nM in NPM-ALK-dependent cells, Ba/F3 NPM-ALK, SU-DHL-1 and Karpas-299, but not the parent Ba/F3-WT cells, with a dose-dependent reduction of NPM-ALK auto-phosphorylation. Through the inhibition of NPM-ALK kinase activity, the downstream signaling events, pSTAT3-Y705 and pSTAT5-Y694, were inhibited in a concentration- (>50nM) and time (50nM, >15min)-dependent manner in Ba/F3 NPM-ALK and Karpas-299 cells. Also, NVP-TAE 684 (>50nM) can lead a dose-dependent reduction in phosphorylation of both ERK and Akt in Karpas-299 cells after 4h of treatment. The G1 phase arrest and apoptosis induced by treatment with 50nM NVP-TAE 684 for 48h can be observed in NPM-ALK-expressing Ba/F3 cells and ALCL patient cell lines. Oral administration of NVP-TAE 684 at dose of 3 and 10mg/kg once daily for 4 weeks significantly delayed lymphoma development in Karpas-299 xenograft mice. Daily oral administration of NVP-TAE 684 at dose of 5 or 10mg/kg for 2 weeks initiated 12 days after Karpas-299 inoculation induced disease regression in mice. Reduction of p-ALK and p-STAT3, as well as CD30 expression (present as the ALCLs) can be observed at day 3 after dose[1].
作用机制
NVP-TAE 684 is expected to bind with the ATP-binding site of ALK.[1]
NVP-TAE 684 细胞实验
Cell Line
Concentration
Treated Time
Description
References
CLB-GA cell line
300 nM
6 h
Inhibition of ALK activity, leading to decreased RET mRNA levels
Oncogene. 2018 Mar;37(11):1417-1429.
CLB-MA cell line
300 nM
6 h
Inhibition of ALK activity, leading to decreased RET mRNA levels
Oncogene. 2018 Mar;37(11):1417-1429.
H3122 cells
100nM
6 h
To evaluate the effect of ALK inhibitor on PI3K signaling
Inhibits ALK receptor, reduces SOX9 protein levels, and decreases self-renewal capacity of GICs
Theranostics. 2020 Apr 6;10(11):5120-5136.
KB-CV60 cells
0.2 µM and 0.5 µM
72 h
To evaluate the reversal effect of NVP-TAE684 on ABCC1-mediated multidrug resistance. Results showed that NVP-TAE684 did not significantly reverse ABCC1-mediated resistance.
Front Oncol. 2020 Feb 27;10:228.
HEK293/ABCG2 cells
0.2 µM and 0.5 µM
72 h
To evaluate the reversal effect of NVP-TAE684 on ABCG2-transfected cells. Results showed that NVP-TAE684 significantly decreased the resistance in ABCG2-transfected cells.
Front Oncol. 2020 Feb 27;10:228.
NCI-H460/MX20 cells
0.2 µM and 0.5 µM
72 h
To evaluate the reversal effect of NVP-TAE684 on ABCG2-mediated multidrug resistance. Results showed that NVP-TAE684 significantly decreased the resistance in ABCG2-overexpressing cells.
Front Oncol. 2020 Feb 27;10:228.
SK-N-BE(2)C cell line
300 nM
6 h
Inhibition of ALK activity, leading to a slight decrease in RET mRNA levels
Oncogene. 2018 Mar;37(11):1417-1429.
Neuroblastoma cells (LS cells)
1 μM
24 h
Inhibition of ALK activity, reduction of pY-GSK3 expression, affecting cell migration
Nat Commun. 2018 Mar 19;9(1):1126.
Neuroblastoma cells (Kelly cells)
1 μM
24 h
Inhibition of ALK activity, reduction of pY-GSK3 expression, affecting cell migration
Nat Commun. 2018 Mar 19;9(1):1126.
NVP-TAE 684 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Cocaine sensitization and conditioned place preference model
Oral gavage
10 mg/kg
Once daily for 7 days
To evaluate the effect of TAE684 on cocaine-induced behavioral responses, results showed TAE684 delayed cocaine sensitization and reduced conditioned place preference
J Neurosci. 2011 Oct 5;31(40):14134-41
Nude mice
H3122 lung cancer xenograft model
Orogastric gavage
25 mg/kg/d
Once daily for 2 days
To evaluate the effect of TAE-684 on tumor growth and PI3K signaling
搜索
