title: SU11652 Inhibits tyrosine kinase activity of FLT3 and growth of MV-4-11 cells.
abstract: BACKGROUND
  FLT3-ITD and FLT3-TKD mutations are frequently found in acute myeloid leukemia (AML). This makes tyrosine kinase FLT3 a highly attractive target for therapeutic drug development. However, effective drugs have not yet emerged. This study is intended to identify and to characterize new FLT3 inhibitors.
  
  
  METHODS
  By using the protein substrate GST-FLT3S to analyze kinase activity of recombinant proteins carrying the catalytic domain of wild type and mutant forms of FLT3, we screened a chemical library containing 80 known protein kinase inhibitors. We identified SU11652 as a potent FLT3 inhibitor and further employed FLT3-ITD-positive MV- 4-11 cells to study its effects on cell growth, apoptosis, cell cycles, and cell signaling.
  
  
  RESULTS
  SU11652 strongly inhibited the activity of wild type, D835Y, and D835H mutant forms of FLT3 with IC50 values of 1.5, 16, and 32 nM, respectively. It effectively blocked the growth of FLT3-ITD -positive MV-4-11 cells at nanomolar concentrations but exhibited much less effects on several other cells which do not carry mutations of FLT3. SU11652 inhibited growth of MV-4-11 cells by inducing apoptosis, causing cell cycle arrest, and blocking activation of the ERK, Akt, and STAT signaling pathways.
  
  
  CONCLUSIONS
  SU11652 is a potent FLT3 inhibitor which selectively targets FLT3-ITD-positive cells. It should serve as a good candidate for development of therapeutic drugs to treat AML.
authors.affiliation: Edmond H, Fischer Signal Transduction Laboratory, College of Life Sciences, Jilin University, Changchun, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Guo
authors.forename: Yun
authors.initials: Y
authors.lastname: Chen
authors.forename: Xuesong
authors.initials: X
authors.lastname: Xu
authors.forename: Xueqi
authors.initials: X
authors.lastname: Fu
authors.forename: Zhizhuang Joe
authors.initials: ZJ
authors.lastname: Zhao
mesh_terms: D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C464576:SU 11652; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3