5-フルオロ-2-[[(S)-1-(4-フルオロフェニル)エチル]アミノ]-6-[(5-メチル-1H-ピラゾール-3-イル)アミノ]ニコチノニトリル

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説明

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). Furthermore, constitutive activation of the JAK2 signaling pathway is associated with aggressive adult T cell leukemia/lymphoma. AZ 960 inhibits JAK2 with a Ki value of 0.45 nM in vitro. 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 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.