Investigational New Drugs

, Volume 29, Issue 5, pp 818–826

Preclinical characterization of atiprimod, a novel JAK2 AND JAK3 inhibitor

  • Alfonso Quintás-Cardama
  • Taghi Manshouri
  • Zeev Estrov
  • David Harris
  • Ying Zhang
  • Amos Gaikwad
  • Hagop M. Kantarjian
  • Srdan Verstovsek
PRECLINICAL STUDIES

DOI: 10.1007/s10637-010-9429-z

Cite this article as:
Quintás-Cardama, A., Manshouri, T., Estrov, Z. et al. Invest New Drugs (2011) 29: 818. doi:10.1007/s10637-010-9429-z

Summary

We herein report on the activity of the JAK2/JAK3 small molecule inhibitor atiprimod on mouse FDCP-EpoR cells carrying either wild-type (JAK2WT) or mutant (JAK2V617F) JAK2, human acute megakaryoblastic leukemia cells carrying JAK2V617F (SET-2 cell line), and human acute megakaryocytic leukemia carrying mutated JAK3 (CMK cells). Atiprimod inhibited more efficaciously the proliferation of FDCP-EpoR JAK2V617F (IC50 0.42 μM) and SET-2 cells (IC50 0.53 μM) than that of CMK (IC50 0.79 μM) or FDCP-EpoR JAK2WT cells (IC50 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 JAK2V617F–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 JAK2V617F-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 JAK2V617F 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.

Keywords

Atiprimod JAK inhibitor JAK2 mutation FDCP cells Megakaryoblastic cells Polycythemia vera Myeloproliferative neoplasia 

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Alfonso Quintás-Cardama
    • 1
  • Taghi Manshouri
    • 1
  • Zeev Estrov
    • 1
  • David Harris
    • 1
  • Ying Zhang
    • 1
  • Amos Gaikwad
    • 2
  • Hagop M. Kantarjian
    • 1
  • Srdan Verstovsek
    • 1
  1. 1.Department of LeukemiaUT MD Anderson Cancer CenterHoustonUSA
  2. 2.Department of Pediatric Hematology/Oncology, Texas Children’s Cancer CenterBaylor College of MedicineHoustonUSA

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