AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia

Erika K. Keeton, Kristen McEachern, Keith S. Dillman, Sangeetha Palakurthi, Yichen Cao, Michael R. Grondine, Surinder Kaur, Suping Wang, Yuching Chen, Allan Wu, Minhui Shen, Francis D. Gibbons, Michelle L. Lamb, Xiaolan Zheng, Richard M. Stone, Daniel J. DeAngelo, Leonidas C. Platanias, Les A. Dakin, Huawei Chen, Paul D. LyneDennis Huszar*

*Corresponding author for this work

Research output: Contribution to journalArticle

148 Scopus citations

Abstract

Upregulation of Pim kinases is observed in several types of leukemias and lymphomas. Pim-1, -2, and -3 promote cell proliferation and survival downstream of cytokine and growth factor signaling pathways. AZD1208 is a potent, highly selective, and orally available Pim kinase inhibitor that effectively inhibits all three isoforms at <5 nM or <150 nM in enzyme and cell assays, respectively. AZD1208 inhibited the growth of 5 of 14 acute myeloid leukemia (AML) cell lines tested, and sensitivity correlates with Pim-1 expression and STAT5 activation. AZD1208 causes cell cycle arrest and apoptosis in MOLM-16 cells, accompanied by a dose-dependent reduction in phosphorylation of Bcl-2 antagonist of cell death, 4EBP1, p70S6K, andS6, aswell as increases in cleaved caspase 3 and p27. Inhibition of p4EBP1 and p-p70S6K and suppression of translation are the most representative effects of Pim inhibition in sensitive AML cell lines. AZD1208 inhibits the growth of MOLM-16 and KG-1a xenograft tumors in vivo with a clear pharmacodynamic-pharmacokinetic relationship. AZD1208 also potently inhibits colony growth and Pim signaling substrates in primary AML cells from bonemarrow that are Flt3 wild-type or Flt3 internal tandem duplication mutant. These results underscore the therapeutic potential of Pim kinase inhibition for the treatment of AML.

Original languageEnglish (US)
Pages (from-to)905-913
Number of pages9
JournalBlood
Volume123
Issue number6
DOIs
StatePublished - Feb 6 2014

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Keeton, E. K., McEachern, K., Dillman, K. S., Palakurthi, S., Cao, Y., Grondine, M. R., Kaur, S., Wang, S., Chen, Y., Wu, A., Shen, M., Gibbons, F. D., Lamb, M. L., Zheng, X., Stone, R. M., DeAngelo, D. J., Platanias, L. C., Dakin, L. A., Chen, H., ... Huszar, D. (2014). AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia. Blood, 123(6), 905-913. https://doi.org/10.1182/blood-2013-04-495366