title: ABT-869, a multitargeted receptor tyrosine kinase inhibitor: inhibition of FLT3 phosphorylation and signaling in acute myeloid leukemia.
abstract: In 15% to 30% of patients with acute myeloid leukemia (AML), aberrant proliferation is a consequence of a juxtamembrane mutation in the FLT3 gene (FMS-like tyrosine kinase 3-internal tandem duplication [FLT3-ITD]), causing constitutive kinase activity. ABT-869 (a multitargeted receptor tyrosine kinase inhibitor) inhibited the phosphorylation of FLT3, STAT5, and ERK, as well as Pim-1 expression in MV-4-11 and MOLM-13 cells (IC(50) approximately 1-10 nM) harboring the FLT3-ITD. ABT-869 inhibited the proliferation of these cells (IC(50) = 4 and 6 nM, respectively) through the induction of apoptosis (increased sub-G(0)/G(1) phase, caspase activation, and PARP cleavage), whereas cells harboring wild-type (wt)-FLT3 were less sensitive. In normal human blood spiked with AML cells, ABT-869 inhibited phosphorylation of FLT3 (IC(50) approximately 100 nM), STAT5, and ERK, and decreased Pim-1 expression. In methylcellulose-based colony-forming assays, ABT-869 had no significant effect up to 1000 nM on normal hematopoietic progenitor cells, whereas in AML patient samples harboring both FLT3-ITD and wt-FLT3, ABT-869 inhibited colony formation (IC(50) = 100 and 1000 nM, respectively). ABT-869 dose-dependently inhibited MV-4-11 and MOLM-13 flank tumor growth, prevented tumor formation, regressed established MV-4-11 xenografts, and increased survival by 20 weeks in an MV-4-11 engraftment model. In tumors, ABT-869 inhibited FLT3 phosphorylation, induced apoptosis (transferase-mediated dUTP nick-end labeling [TUNEL]) and decreased proliferation (Ki67). ABT-869 is under clinical development for AML.
authors.affiliation: Division of Hematology/Oncology, Department of Pediatrics, Gwynne Hazen Cherry Memorial Laboratories, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA. keith.glaser@abbott.com
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authors.forename: Ru-Qi
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authors.forename: Michael R
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authors.lastname: Michaelides
authors.forename: Steven K
authors.initials: SK
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authors.forename: Saul J
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authors.lastname: Priceman
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Chang
authors.forename: Katrin
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authors.forename: Neil
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authors.forename: Theodore B
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authors.lastname: Moore
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authors.lastname: Sakamoto
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authors.lastname: Glaser
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D020014:K562 Cells; D019394:Ki-67 Antigen / Q000096:biosynthesis; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology; D051379:Mice; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D051573:Proto-Oncogene Proteins c-pim-1; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D050799:STAT5 Transcription Factor / Q000378:metabolism; D014410:Tumor Stem Cell Assay; D020298:U937 Cells; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism*
chemical_list: D007191:Indazoles; D019394:Ki-67 Antigen; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D050799:STAT5 Transcription Factor; C513486:linifanib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1; D048049:Extracellular Signal-Regulated MAP Kinases