AZ 960

AZ-960 is a potent, selective and ATP-competitive JAK2 inhibitor that inhibits JAK2 kinase with a Ki of 0.45nM in vitro (3-fold selective over JAK3) and induces growth arrest and apoptosis in adult T cell leukemia (ATL) cells. 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 position 617 (V617F). Furthermore, constitutive activation of the JAK2 signaling pathway is associated with aggressive adult T cell leukemia/lymphoma. AZ-960 induces growth arrest and apoptosis of human T cell lymphotropic virus type 1, HTLV-1-infected T cells (MT-1 and MT-2) in parallel with downregulation of the phosphorylated forms of JAK2 and Bcl-2 family proteins including Bcl-2 and Mcl-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. AZ-960 shows anti-parasitic activity through selective inhibition of the Trypanosoma brucei ERK8 inhibitor (TbERK8).