Title:Insights into the Structural Features Essential for JAK2 Inhibition and Selectivity
Volume: 23
Issue: 13
Author(s): Chao Zhao, Daulat Bikram Khadka and Won-Jea Cho
Affiliation:
Keywords:
Hinge region, Janus kinase 2, type I JAK2 inhibitor, JAK2V617F mutation, JAK isoenzymes selectivity,
myeloproliferative neoplasm.
Abstract: The Janus kinase 2 (JAK2)-mediated signaling pathway plays an important role in
controlling cell survival, proliferation, and differentiation. A mutation of JAK2 (V617F in
specific) that results in constitutive activation of the enzyme is found in patients with myeloproliferative
neoplasms (MPNs), such as polycythemia vera (PV), essential thrombocythemia,
and primary myelofibrosis. The genetic, biological, and physiological evidence
available to date has established JAK2 inhibitors as effective chemotherapeutic agents for
the treatment of MPNs as well as solid tumors, hepatitis C virus (HCV) infection, Alzheimer’s
disease, and Parkinson’s disease. Important features essential for JAK2 inhibitors are potent enzymatic
inhibition and a high degree of selectivity among other isoforms of JAK. The extent of the potency and
selectivity of JAK2 inhibitors is dependent upon receptor-ligand interactions and structural difference between
isoenzymes. Thus, detailed knowledge regarding structural characteristics and the binding mode between
JAK2 and its inhibitors is necessary. Accordingly, we compiled in this review a comprehensive summary
of the three dimensional (3D) structural features of reported JAK2-ligand complexes and the structureactivity
relationship (SAR) of JAK2 inhibitors, with particular focus on potent JAK2 inhibition and specificity.
