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

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, and S6, as well 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 bone marrow 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.

• Authors: 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 Lyne, Dennis Huszar
• Journal: Blood (Blood) Vol. 123 Issue 6 Pg. 905-13 (Feb 06 2014) ISSN: 1528-0020 [Electronic] United States
• PMID: 24363397 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• AZD1208
• Biphenyl Compounds
• Protein Kinase Inhibitors
• Thiazolidines
• PIM1 protein, human
• Proto-Oncogene Proteins c-pim-1

Topics

• Animals
• Apoptosis (drug effects)
• Biphenyl Compounds (pharmacokinetics, pharmacology)
• Blotting, Western
• Cell Cycle
• Cell Proliferation (drug effects)
• Enzyme-Linked Immunosorbent Assay
• Female
• Humans
• Leukemia, Myeloid, Acute (drug therapy, enzymology, pathology)
• Mice
• Mice, SCID
• Protein Kinase Inhibitors (pharmacokinetics, pharmacology)
• Proto-Oncogene Proteins c-pim-1 (antagonists & inhibitors, metabolism)
• Thiazolidines (pharmacokinetics, pharmacology)
• Tissue Distribution
• Tumor Cells, Cultured