Characterization of the aminopyridine derivative KRC-180 as a JAK2 inhibitor.

ABSTRACT

Janus kinase 2 (JAK2) is a non-receptor tyrosine kinase that regulates the signal transducer and activator of transcription (STAT) signaling pathway. Deregulation of JAK2 signaling has previously been observed in hematologic malignancies, including erythroleukemia. In the present study, an aminopyridine derivative compound, KRC-180, exhibited direct inhibition of the JAK2 protein at the catalytic site, as demonstrated using in vitro kinase activity assays and docking analyses. In addition, KRC-180 reduced the phosphorylation of STAT3 and STAT5, downstream signaling molecules of JAK2. The growth of HEL92.1.7 erythroleukemia cells harboring a constitutively activated form of JAK2 was suppressed by KRC-180 treatment; KRC-180 induced apoptotic cell death and cell cycle arrest. The results of the present study indicate that KRC-180 is a JAK2 inhibitor with anti-leukemic properties.