FLT3 inhibitors: a story of the old and the new.
OBJECTIVE
Ever since the recognition that FMS-like tyrosine kinase 3 (FLT3) mutations exert a profound negative prognostic impact on the clinical outcome of patients with acute myeloid leukemia (AML), researchers have sought to find effective small-molecule inhibitors of this receptor tyrosine kinase. This review will attempt to provide a survey of the FLT3 inhibitors currently under investigation and provide a discussion on their current status in clinical trials.


RESULTS
Over the past 10 years, a number of different compounds have been studied in vitro and clinically as FLT3 inhibitors. The first inhibitors studied were hampered by cumbersome pharmacokinetics and a general lack of potency. However, some agents have shown promise in clinical trials with transient responses in AML. Newer compounds, such as AC220, have demonstrated profound selectivity and potency against the FLT3 target, and are currently being investigated in clinical trials.


CONCLUSIONS
Clinical trials have so far demonstrated that inhibitors of FLT3 do have clinical activity in patients with FLT3-mutant AML, although this activity is often transient and correlates with effective in-vivo suppression of the FLT3 target. As newer, more potent agents are now entering advanced clinical trials, opportunities will emerge for real progress against this grim disease.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, USA.
Amir
A
Fathi
Mark
M
Levis
D000208:Acute Disease; D052160:Benzothiazoles / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002986:Clinical Trials as Topic; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009154:Mutation; D010671:Phenylurea Compounds / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics
D052160:Benzothiazoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; C544967:quizartinib; D051941:fms-Like Tyrosine Kinase 3
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