AZD 1480

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).{27171} AZD 1480 is a potent JAK2 inhibitor that blocks signaling (IC50 = 58 nM at 5 mM ATP) and proliferation of JAK2-expressing cell lines (GI50 = 60 nM).{29735,18888} It is selective for JAK2 over other JAK family members as well as a panel of related kinases.{18888} AZD 1480 also inhibits the growth of cells expressing the V617F mutant of JAK2 (GI50 = 60 nM).{18888} It reversibly blocks JAK2-mediated phosphorylation of STAT3 and STAT5.{18888} AZD 1480 displays good pharmacokinetics in vivo, inhibits STAT3 and STAT5 activation in vivo, and suppresses tumorigenesis in mouse xenografts harboring constitutive STAT3 activity.{29735,18888} In addition to suppressing myeloma cell growth and survival, AZD 1480 reduces angiogenesis and metastasis in vitro and in human xenograft tumor models.{29736,29737}