Background:T cell acute lymphoblastic leukemia (T-ALL) is an invasive hematological
malignant disorder of T cell progenitors. The Janus kinase-signal transducer and activator of transcription
(JAK-STAT) signaling pathway plays an important role in the development of T-ALL and in the
inhibition of the key molecule, JAK2, and could suppress T-ALL cell proliferation.Objective:The objective of this study was to investigate the in vitro anti-tumor effects of a novel nilotinib
derivative, ND-17, on cancer cell lines via its interactions with JAK2.Methods:The effects of ND-17 on cell proliferation and on cell cycle and apoptosis were evaluated
using the tetrazolium assay and flow cytometry, respectively. In addition, the ND-17/JAK2 binding
interactions were evaluated using surface plasmon resonance and western blot analyses.Results:ND-17 exerted the greatest inhibitory effects on T-ALL cells amongst all hematological cancer
cell lines tested. Flow cytometric analysis indicated that ND-17 blocked the cell cycle at the S
phase in T-ALL cells. Nilotinib did not significantly inhibit T-ALL cell growth or regulate the cell
cycle. Preliminary investigations revealed that the regulation of cyclin-dependent kinases/cyclins was
attributed to ND-17-induced cell cycle arrest. Furthermore, ND-17 could bind to JAK2 with strong
affinity, and more importantly, ND-17 bound to the ATP pocket of JAK2 in a manner similar to the
potent inhibitor. Thus, ND-17 treatment exhibited a prominent effect in inhibiting the phosphorylation
of JAK2 in T-ALL cells. An increase in the phosphorylation of JAK2 was observed in interleukin-6-
stimulated Jurkat cells, which was reversed by ND-17 treatment. Meanwhile, the combination of TG-
101348 and ND-17 led to further improvement in inhibiting the phosphorylation of JAK2. Moreover,
the transfection and knockdown of JAK2 altered the inhibitory effect of ND-17 on Jurkat cell viability.
In addition, ND-17 treatment suppressed the JAK/STAT, phosphatidylinositol-3-kinase/protein kinase
B/mechanistic target of rapamycin, and mitogen-activated protein kinase/extracellular signal-regulated
protein kinases 1 and 2 signaling pathways.Conclusion:These findings suggest that ND-17 could be a promising JAK2 inhibitor for the treatment
of T-ALL.
