AZ 960

Janus-associated kinases (JAKs) are cytoplasmic tyrosine kinases that are required for activating the signaling of certain cytokines and growth factor receptors. Many myeloproliferative diseases have been linked to a mutation in JAK2 where a switch from valine to phenylalanine occurs at the 617 position (V617F).¹ Furthermore, constitutive activation of the JAK2 signaling pathway is associated with aggressive adult T cell leukemia/lymphoma.² AZ 960 inhibits JAK2 with a K_i value of 0.45 nM in vitro.¹ It can decrease STAT3/5 phosphorylation and inhibit cell proliferation in a SET-2 human megakaryoblastic cell line that is heterozygous for the JAK2 V617F mutation with a GI₅₀ value of 33 nM.¹ AZ 960 can also induce apoptosis in human T cell lymophotropic virus type 1-infected (IC₅₀ = ~1 µM), which corresponds to a downregulation of phosphorylated forms of JAK2 and Bcl-2 family proteins.²

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1. Gozgit, J.M., Bebernitz, G., Patil, P., et al. Effects of the JAK2 inhibitor, AZ960, on Pim/BAD/BCL-xL survival signaling in the human JAK2 V617F cell line SET-2. The Journal of Biological Chemisty 283(47), 32334-32343 (2008).

2. Yang, J., Ikezoe, T., Nishioka, C., et al. AZ960, a novel Jak2 inhibitor, induces growth arrest and apoptosis in adult T-cell leukemia cells. Mol. Cancer Ther. 9(12), 3386-3395 (2010).