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

Expert opinion

Protein phosphorylation balance plays a key role in many physiological processes and is often deregulated in pathological conditions. Our current understanding of how both protein kinases and phosphatases orchestrate phosphorylation changes, which control cellular functions, has made these enzymes obvious drug targets for treating many diseases, particularly cancer.Today’s focus is on kinases. It’s hard to choose among the hundreds of kinases listed in the human kinome, so let’s use Janus Kinase 2 (JAK2) as an example.In 2005, the discovery of a single mutation (V617F) in JAK2 shifted the physiopathological understanding of myeloproliferative neoplasms (MNPs). Since then, the JAK-STAT signaling pathway has been fully dissected and many inhibitors identified. In this article, discover the full characterization of the KRC-180 inhibitor on JAK2. By combining in-silico molecular docking and several in-vitro studies, Kyoung Bin Yoon investigated the mechanism of action of this inhibitor and its derivatives on JAK2 and on the JAK-QTAT pathway.Moving from in-vitro to cell-based assays, he also demonstrated the potency of KRC-180 in HEL92.1.7 cells, a human erythroleukemia cell line naturally harboring the JAK2-V617F mutation.In-silico to in-vitro… in-vitro to in-cellulo… always running two approaches sequentially. The strategy is well suited for JAK2, which takes its name from Janus, the Roman god with two heads.JAK2 is not “”Just Another Kinase””, as it was initially named by researchers. JAK2 still holds many secrets to be revealed and represents a very attractive target for curing hematological disorders. Follow the strategy described here and head down the path for screening new JAK2 inhibitors.

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.