ABT-869, a multitargeted receptor tyrosine kinase inhibitor: inhibition of FLT3 phosphorylation and signaling in acute myeloid leukemia

Blood. 2007 Apr 15;109(8):3400-8. doi: 10.1182/blood-2006-06-029579. Epub 2007 Jan 5.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • G1 Phase / drug effects
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Indazoles / pharmacology*
  • K562 Cells
  • Ki-67 Antigen / biosynthesis
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / enzymology
  • Mice
  • Phenylurea Compounds / pharmacology*
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Processing, Post-Translational / drug effects*
  • Proto-Oncogene Proteins c-pim-1
  • Resting Phase, Cell Cycle / drug effects
  • STAT5 Transcription Factor / metabolism
  • Tumor Stem Cell Assay
  • U937 Cells
  • fms-Like Tyrosine Kinase 3 / metabolism*

Substances

  • Indazoles
  • Ki-67 Antigen
  • N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N1-(2-fluoro-5-methylphenyl)urea
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • STAT5 Transcription Factor
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3
  • PIM1 protein, human
  • Proto-Oncogene Proteins c-pim-1
  • Extracellular Signal-Regulated MAP Kinases