Preclinical characterization of atiprimod, a novel JAK2 AND JAK3 inhibitor

Invest New Drugs. 2011 Oct;29(5):818-26. doi: 10.1007/s10637-010-9429-z. Epub 2010 Apr 7.


We herein report on the activity of the JAK2/JAK3 small molecule inhibitor atiprimod on mouse FDCP-EpoR cells carrying either wild-type (JAK2 (WT)) or mutant (JAK2 (V617F)) JAK2, human acute megakaryoblastic leukemia cells carrying JAK2 (V617F) (SET-2 cell line), and human acute megakaryocytic leukemia carrying mutated JAK3 (CMK cells). Atiprimod inhibited more efficaciously the proliferation of FDCP-EpoR JAK2 (V617F) (IC(50) 0.42 μM) and SET-2 cells (IC(50) 0.53 μM) than that of CMK (IC(50) 0.79 μM) or FDCP-EpoR JAK2 (WT) cells (IC(50) 0.69 μM). This activity was accompanied by inhibition of the phosphorylation of JAK2 and downstream signaling proteins STAT3, STAT5, and AKT in a dose- and time-dependent manner. Atiprimod-induced cell growth inhibition of JAK2 (V617F)-positive cells was coupled with induction of apoptosis, as evidenced by heightened mitochondrial membrane potential and caspase-3 activity, as well as PARP cleavage, increased turnover of the anti-apoptotic X-linked mammalian inhibitor of apoptosis (XIAP) protein, and inhibition of the pro-apoptotic protein BCL-2 in a time- and dose-dependent manner. Furthermore, atiprimod was more effective at inhibiting the proliferation of peripheral blood hematopoietic progenitors obtained from patients with JAK2 (V617F)-positive polycythemia vera than at inhibiting hematopoietic progenitors from normal individuals (p = 0.001). The effect on primary expanded erythroid progenitors was paralleled by a decrease in JAK2(V617F) mutant allele burden in single microaspirated BFU-E and CFU-GM colonies. Taken together, our data supports the clinical testing of atiprimod in patients with hematologic malignancies driven by constitutive activation of JAK2 or JAK3 kinases.

MeSH terms

  • Alleles
  • Animals
  • Apoptosis / drug effects
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Colony-Forming Units Assay
  • Drug Screening Assays, Antitumor
  • Erythroid Precursor Cells / cytology
  • Erythroid Precursor Cells / drug effects
  • Humans
  • Janus Kinase 2 / antagonists & inhibitors*
  • Janus Kinase 2 / metabolism
  • Janus Kinase 3 / antagonists & inhibitors*
  • Janus Kinase 3 / metabolism
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Mutant Proteins / metabolism
  • Mutation / genetics
  • Phosphorylation / drug effects
  • Poly(ADP-ribose) Polymerases / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • STAT Transcription Factors / metabolism
  • Signal Transduction / drug effects
  • Spiro Compounds / pharmacology*
  • X-Linked Inhibitor of Apoptosis Protein / metabolism


  • Mutant Proteins
  • Protein Kinase Inhibitors
  • STAT Transcription Factors
  • Spiro Compounds
  • X-Linked Inhibitor of Apoptosis Protein
  • azaspirane
  • Poly(ADP-ribose) Polymerases
  • Janus Kinase 2
  • Janus Kinase 3
  • Proto-Oncogene Proteins c-akt
  • Caspase 3