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]
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