title: The clinical development of FLT3 inhibitors in acute myeloid leukemia.
abstract: BACKGROUND
  Activating mutations of the FMS-like tyrosine kinase 3 (FLT3) gene occur at high frequency in acute myeloid leukemia (AML), being detected in > 30% of patients at diagnosis and carrying a profound negative prognostic impact. The development of effective small molecule inhibitors of FLT3 has been the focus of an intensive international research effort in recent years.
  
  
  METHODS
  The published results of the first decade of clinical trials of FLT3-targeted tyrosine kinase inhibitors are critically reviewed. Over this period, a first generation of compounds has followed an orderly progression from monotherapy studies through combination with chemotherapy and into advanced stage international trials in both relapsed and newly-diagnosed AML. Correlative laboratory studies performed alongside several of these studies have been highly illuminating, demonstrating close correlations between clinical activity and effective inhibition of FLT3, and highlighting potential drug resistance mechanisms.
  
  
  CONCLUSIONS
  Clinical responses to several of the early multi-targeted agents were hindered by unfavorable pharmacokinetics and lack of potency. Newer, more potent FLT3 inhibitors such as sorafenib and AC220 possess the ability to achieve more sustained in vivo inhibition of FLT3 and have shown highly promising activity in early clinical studies. As these agents enter advanced stage trials, they carry the potential to make a major clinical impact in this disease. In future, FLT3 inhibitors may be effectively used in combination with other molecularly targeted agents.
authors: Cardiff University, University Hospital of Wales, Department of Haematology, Heath Park, Cardiff, CF14 4XW, UK. knappers@cf.ac.uk
authors: Steven
authors: S
authors: Knapper
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3