1. AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia.
- Author
-
Keeton EK, McEachern K, Dillman KS, Palakurthi S, Cao Y, Grondine MR, Kaur S, Wang S, Chen Y, Wu A, Shen M, Gibbons FD, Lamb ML, Zheng X, Stone RM, Deangelo DJ, Platanias LC, Dakin LA, Chen H, Lyne PD, and Huszar D
- Subjects
- Animals, Biphenyl Compounds pharmacokinetics, Blotting, Western, Cell Cycle, Enzyme-Linked Immunosorbent Assay, Female, Humans, Leukemia, Myeloid, Acute enzymology, Leukemia, Myeloid, Acute pathology, Mice, Mice, SCID, Protein Kinase Inhibitors pharmacokinetics, Proto-Oncogene Proteins c-pim-1 metabolism, Thiazolidines pharmacokinetics, Tissue Distribution, Tumor Cells, Cultured, Apoptosis drug effects, Biphenyl Compounds pharmacology, Cell Proliferation drug effects, Leukemia, Myeloid, Acute drug therapy, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-pim-1 antagonists & inhibitors, Thiazolidines pharmacology
- 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.
- Published
- 2014
- Full Text
- View/download PDF