The Janus-associated kinase (Jak) family, comprised 4 different protein-tyrosine kinases, Jak1, Jak2, Jak3, and TYK2, plays an important role in cellular survival, proliferation, and differentiation. Jak kinases are key mediators of signaling downstream of a variety of cytokine and/or growth factor receptors. Each Jak possesses kinase domain, a catalytically inactive pseudokinase, and amini-terminal, ezrin, radixin, and moesin (FERM). Cytokine receptors bind to FERM domain, leading to activation of Jaks, which create docking sites for members of signal transducers and activators of transcription (Stat) family, including Stat3 and Stat5. AZ960 is a potent and selective ATP competitive inhibitor of the Jak2 kinase with a Ki of 0.45 nM. AZ960 was also shown to be active against other kinases, including TrkA, Aurora-A, and FAK, with IC50 of around 0.1 μM. In a vitro study, HTLV-1 (human T-cell lymphotropic virus type 1) - infected T cells cells were incubated with AZ960 (0.3 or 1 μM) for 2 days and the result showed that AZ960 suppressed the growth of MT-1 and MT-2 cells with IC50 of 0.8 and 1 μM. Intact GV-oocytes were cultured with CEP-33779 for 12 h to inhibit JAK2 activity during maturation. The result showed that a large proportion of the CEP-33779 treated oocytes failed to extrude polar body I, only 21.14 ± 4.03% (n=382) of these oocytes reached the M II stage after 12 h in vitro maturation, a rate significantly lower than that of non-treated control oocytes (81.44±3.64%, n=357)[3]. HTLV-1-infected T cells and MOLT-4 cells (5 × 105 cells/mL) were cultured with various concentrations of AZ960 (0.03-1 μM) for 2 days. AZ960 inhibited the growth of freshly isolated ATL (Adult T-cell leukemia/lymphoma) cells in a dose-dependent manner with IC50 of 0.3 μM, and AZ960 also inhibited the growth of MOLT-4 cells in a dose-dependent manner with IC50 of 1.2 μM, which indicated blockade of Jak2/Stats by Jak2 kinase inhibitor AZ960 represents a promising treatment strategy for individuals with ATL.
作用机制
AZ 960 binds to the ATP-binding site of JAK2 kinase.
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