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Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Insights into the Structural Features Essential for JAK2 Inhibition and Selectivity

Author(s): Chao Zhao, Daulat Bikram Khadka and Won-Jea Cho

Volume 23, Issue 13, 2016

Page: [1331 - 1355] Pages: 25

DOI: 10.2174/0929867323666160405112615

Price: $65


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.

Keywords: Hinge region, Janus kinase 2, type I JAK2 inhibitor, JAK2V617F mutation, JAK isoenzymes selectivity, myeloproliferative neoplasm.

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