Identification of a novel inhibitor of JAK2 tyrosine kinase by structure-based virtual screening

Abstract

Janus kinase 2 (JAK2) plays a crucial role in the pathomechanism of myeloproliferative disorders and hematologic malignancies. A somatic mutation of JAK2 (Val617Phe) was previously shown to occur in 98% of patients with polycythemia vera and 50% of patients with essential thrombocythemia and primary myelofibrosis. Thus, effective JAK2 kinase inhibitors may be of significant therapeutic importance. Here, we applied a structure-based virtual screen to identify novel JAK2 inhibitors. One JAK2 inhibitor in particular, G6, demonstrated remarkable potency as well as specificity, which makes it as a potential lead candidate against diseases related to elevated JAK2 tyrosine kinase activity.

Figure 1

Inhibition of JAK2 Val617Phe kinase activity by G6 (IC₅₀ = 60 ± 4.5 nM).

Figure 2

Growth inhibitory effect of G6 on HEL, CMK, Raji and BSC-40 cells.

Figure 3

Growth inhibition of G6 on cells from polycythemia vera patient.

Figure 4

Binding mode of G6 (gray) at the JAK2 binding site (green). Van der Waals surface of the most important residues are shown and colored by their electrostatic potential. Picture was generated by MAESTRO.