title: 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.affiliation: Oncology iMed, AstraZeneca, Waltham, MA;
authors.forename: Erika K
authors.initials: EK
authors.lastname: Keeton
authors.forename: Kristen
authors.initials: K
authors.lastname: McEachern
authors.forename: Keith S
authors.initials: KS
authors.lastname: Dillman
authors.forename: Sangeetha
authors.initials: S
authors.lastname: Palakurthi
authors.forename: Yichen
authors.initials: Y
authors.lastname: Cao
authors.forename: Michael R
authors.initials: MR
authors.lastname: Grondine
authors.forename: Surinder
authors.initials: S
authors.lastname: Kaur
authors.forename: Suping
authors.initials: S
authors.lastname: Wang
authors.forename: Yuching
authors.initials: Y
authors.lastname: Chen
authors.forename: Allan
authors.initials: A
authors.lastname: Wu
authors.forename: Minhui
authors.initials: M
authors.lastname: Shen
authors.forename: Francis D
authors.initials: FD
authors.lastname: Gibbons
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Lamb
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Zheng
authors.forename: Richard M
authors.initials: RM
authors.lastname: Stone
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Deangelo
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
authors.forename: Les A
authors.initials: LA
authors.lastname: Dakin
authors.forename: Huawei
authors.initials: H
authors.lastname: Chen
authors.forename: Paul D
authors.initials: PD
authors.lastname: Lyne
authors.forename: Dennis
authors.initials: D
authors.lastname: Huszar
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle; D049109:Cell Proliferation / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053778:Thiazolidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: C587575:AZD1208; D001713:Biphenyl Compounds; D047428:Protein Kinase Inhibitors; D053778:Thiazolidines; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1