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Preclinical characterization of atiprimod, a novel JAK2 AND JAK3 inhibitor

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Summary

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 (IC50 0.42 μM) and SET-2 cells (IC50 0.53 μM) than that of CMK (IC50 0.79 μM) or FDCP-EpoR JAK2 WT 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 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 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.

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Authors and Affiliations

  1. Department of Leukemia, UT MD Anderson Cancer Center, Unit 428, 1515 Holcombe Blvd., Houston, TX, 77030, USA

    Alfonso Quintás-Cardama, Taghi Manshouri, Zeev Estrov, David Harris, Ying Zhang, Hagop M. Kantarjian & Srdan Verstovsek

  2. Department of Pediatric Hematology/Oncology, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX, USA

    Amos Gaikwad

Authors
  1. Alfonso Quintás-Cardama
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  2. Taghi Manshouri
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  3. Zeev Estrov
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  4. David Harris
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  5. Ying Zhang
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  6. Amos Gaikwad
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  7. Hagop M. Kantarjian
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  8. Srdan Verstovsek
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Correspondence to Srdan Verstovsek.

Additional information

Alfonso Quintás-Cardama and Taghi Manshouri contributed equally to this report

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Quintás-Cardama, A., Manshouri, T., Estrov, Z. et al. Preclinical characterization of atiprimod, a novel JAK2 AND JAK3 inhibitor. Invest New Drugs 29, 818–826 (2011). https://doi.org/10.1007/s10637-010-9429-z

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  • DOI: https://doi.org/10.1007/s10637-010-9429-z

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