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

Bioorg Med Chem Lett. 2009 Jul 1;19(13):3598-601. doi: 10.1016/j.bmcl.2009.04.138. Epub 2009 May 5.

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.

MeSH terms

  • Alkenes / chemistry*
  • Alkenes / pharmacology
  • Catalytic Domain
  • Cell Line, Tumor
  • Computer Simulation
  • Crystallography, X-Ray
  • Drug Evaluation, Preclinical
  • Humans
  • Janus Kinase 2 / antagonists & inhibitors*
  • Janus Kinase 2 / metabolism
  • Mutant Proteins / antagonists & inhibitors
  • Mutant Proteins / metabolism
  • Phenols / chemistry*
  • Phenols / pharmacology
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Structure-Activity Relationship

Substances

  • Alkenes
  • Mutant Proteins
  • Phenols
  • Protein Kinase Inhibitors
  • Janus Kinase 2